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Mesenchymal stem cells to treat diabetic neuropathy: a long and strenuous way from bench to the clinic


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As one of the most common complications of diabetes, diabetic neuropathy often causes foot ulcers and even limb amputations. Inspite of continuous development in antidiabetic drugs, there is still no efficient therapy to cure diabetic neuropathy. Diabetic neuropathy shows declined vascularity in peripheral nerves and lack of angiogenic and neurotrophic factors. Mesenchymal stem cells (MSCs) have been indicated as a novel emerging regenerative therapy for diabetic neuropathy because of their multipotency. We will briefly review the pathogenesis of diabetic neuropathy, characteristic of MSCs, effects of MSC therapies for diabetic neuropathy and its related mechanisms. In order to treat diabetic neuropathy, neurotrophic or angiogenic factors in the form of protein or gene therapy are delivered to diabetic neuropathy, but therapeutic efficiencies are very modest if not ineffective. MSC treatment reverses manifestations of diabetic neuropathy. MSCs have an important role to repair tissue and to lower blood glucose level. MSCs even paracrinely secrete neurotrophic factors, angiogenic factors, cytokines, and immunomodulatory substances to ameliorate diabetic neuropathy. There are still several challenges in the clinical translation of MSC therapy, such as safety, optimal dose of administration, optimal mode of cell delivery, issues of MSC heterogeneity, clinically meaningful engraftment, autologous or allogeneic approach, challenges with cell manufacture, and further mechanisms.
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Mesenchymal stem cells to treat diabetic neuropathy:
a long and strenuous way from bench to the clinic
JY Zhou
, Z Zhang
and GS Qian
As one of the most common complications of diabetes, diabetic neuropathy often causes foot ulcers and even limb amputations.
Inspite of continuous development in antidiabetic drugs, there is still no efcient therapy to cure diabetic neuropathy. Diabetic
neuropathy shows declined vascularity in peripheral nerves and lack of angiogenic and neurotrophic factors. Mesenchymal stem
cells (MSCs) have been indicated as a novel emerging regenerative therapy for diabetic neuropathy because of their multipotency.
We will briey review the pathogenesis of diabetic neuropathy, characteristic of MSCs, effects of MSC therapies for diabetic
neuropathy and its related mechanisms. In order to treat diabetic neuropathy, neurotrophic or angiogenic factors in the form of
protein or gene therapy are delivered to diabetic neuropathy, but therapeutic efciencies are very modest if not ineffective. MSC
treatment reverses manifestations of diabetic neuropathy. MSCs have an important role to repair tissue and to lower blood glucose
level. MSCs even paracrinely secrete neurotrophic factors, angiogenic factors, cytokines, and immunomodulatory substances to
ameliorate diabetic neuropathy. There are still several challenges in the clinical translation of MSC therapy, such as safety, optimal
dose of administration, optimal mode of cell delivery, issues of MSC heterogeneity, clinically meaningful engraftment, autologous
or allogeneic approach, challenges with cell manufacture, and further mechanisms.
Cell Death Discovery (2016) 2, e16055; doi:10.1038/cddiscovery.2016.55; published online 11 July 2016
Diabetic neuropathy (DN) often causes foot ulcers and even
limb amputations, without efcient therapy.
DN shows declined vascularity in peripheral nerves and lack of
angiogenic and neurotrophic factors.
Preclinical and clinical studies indicate that mesenchymal stem
cell (MSC) therapy restores manifestations of DN.
What is the exact molecular mechanism of MSCs on DN?
Are there any molecules secreted by MSCs to protect bone
marrow nerve and to maintain bone marrow homeostasis?
Which challenges would be most difcult in the clinical
translation of MSC therapy?
DN is one of the most frequent complications of diabetes, 66% for
type 1 diabetes and 59% for type 2 diabetes.
The pathophysiology
of DN is complicated and not fully elucidated that involves both
vascular and neural components. DN is a systemic and progressive
disorder and its manifestations need many years to develop.
Intervention with tight blood glucose control and treatment with
aldose reductase inhibitor or α-lipoic acid successfully inhibit
the progression of DN,
but no established curable treatment is
available during the progressive stage. During the past decades, one
of the innovative preclinical study has applied gene therapy or MSC
therapy to DN in animal models,
but gene therapy shows weak
result or is ineffective.
MSCs have been believed as a promising regenerative therapy
for DN because of their multipotency and their paracrine secretion
of angiogenic factors and neurotrophic factors. Umbilical cord
blood ex vivo expanded CD34 and umbilical cord matrix MSCs
were well tolerated without adverse effects in a 29-year-old male.
MSC therapies offer more benets than other cell-based therapies.
Practically, as the safety of autologous bone marrow-derived MSCs
(BMSCs) have been documented by variety of clinical trials,
it is
highly recommended to use this strategy in a pilot clinical trial for
those who are severely affected by DN. In this review, we will briey
summarize the pathogenetic mechanisms, effects of MSC treatment,
and challenges from bench to bedside studies of MSCs on DN.
DN is characterized with progressive neuronal loss, demyelination,
and damaged nerve regeneration with ultimately dysfunction of
nerve bers impairing both the autonomic and somatic divisions
of the nervous system.
The pathogenesis of DN is complex but
the same as other complications, hyperglycemia exacerbates its
development. Hyperglycemia damages neurons, Schwann cells,
and endothelial cells of the vasa nervorum in the peripheral
nerves. Hyperglycemia results in oxidative stress, reactive oxygen
species generation, and advance glycation end product produc-
tion, which leads to impairment in sensory, motor, and autonomic
Several factors involve in the development and progres-
sion of DN (Figure 1).
National Drug Clinical Trial Institution, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China and
Institute of Respiratory Diseases, Xinqiao Hospital, Third
Military Medical University, Chongqing, 400037, China.
Correspondence: GS Qian (
Received 24 March 2016; revised 23 May 2016; accepted 11 June 2016; Edited by AE Sayan
Citation: Cell Death Discovery (2016) 2, e16055; doi:10.1038/cddiscovery.2016.55
Ofcial journal of the Cell Death Differentiation Association
Role of neurotrophic factors in pathogenesis
Except the classical major pathophysiological role of neuro-
trophic factors and vascular supply in DN, the two widely
considered downstream consequences of the cellular mechan-
isms are the loss of neurotrophic support and ischemic
hypoxia. Direct cellular contact is not necessary to provide
Critical in providing a protective micro-
environment, neurotrophic factors are growth factors known to
promote neuron development and survival. They also maintain
functional integrity, promote regeneration, regulate neuronal
plasticity, and aid in the repairing of damaged nerves.
various protective types of neurotrophic factors affect different
cell populations within the peripheral and central nervous
Deciency of these neurotrophic factors can cause development
of DN.
Diabetes reduces brain-derived nerve factor (BDNF), nerve
growth factor (NGF), and neurotrophin 3 in peripheral nerves by
limiting anterograde and retrograde axonal transport. Intrathecal
delivery of NGF or neurotrophin 3 improves myelinated ber
innervation in the dermal footpad of diabetic mice, and thus lack
of neurotrophic support affect ber morphology. Neurotrophic
factors may regulate angiogenesis. BDNF is an essential factor
in maintaining cardiac vessel-wall stability during development.
NGF stimulates angiogenesis indirectly by increasing the expres-
sion of (vascular endothelial growth factor (VEGF) and directly
by promoting vascular cell growth. Both neurotrophin 3 (through
binding to TrkC) and leukemia-inhibitory factor serve as inhibitors
of the growth of some endothelial cells.
Role of angiogenic factors in pathogenesis
Many representative growth factors VEGF, insulin-like growth
factor, NGF, BDNF, and broblast growth factor-2 (FGF2, also
known as bFGF) have dual effects of being both neurotrophic and
angiogenic. These growth factor levels are decreased in diabetic
animals and are associated with neural function.
VEGF, a major angiogenic factor, is a potent selective
mitogenic cytokine for endothelial cells. VEGF enhances migra-
tion and proliferation of Schwann cells and promotes axonal
outgrowth and survival of both the neurons and Schwann cells
of superior cervical ganglia and dorsal root ganglia. Insulin-like
growth factors promote neurite outgrowth of neuroblastoma
cells, accelerate regeneration of sensory and motor nerves,
and stimulate Schwann cell mitogenesis and myelination. NGF
provides neuroprotective, repair functions, and directly induces
angiogenesis via promoting survival and differentiation of
sensory and sympathetic neurons.
NGF homozygous knockout
mice do not develop proper sympathetic neurons or small neural
crest-derived sensory neurons.
MSC classication
MSCs have the capacity of self-renewal and the potential
to differentiate into multiple cell types such as adipocytes,
chondrocytes, and osteoblasts, myocytes, and neurons.
MSCs can be derived from bone marrow, adipose tissue, nervous
tissue, amniotic uid, umbilical cord, placenta, menstrual blood,
and dental pulps.
BMSCs and adipose tissue-derived MSCs
are representativeof this.
MSCs are a subset of cells that express on their surface CD54/CD102,
CD166, and CD49 as well as CD73 and CD90. They also express
CD44 and CD105, whereas they do not express CD34, CD14,
CD45, CD11a/LFA-1, and CD31, which are surface markers of
hematopoietic cells and/or endothelial cells.
Although their
differentiation capacity is less than other cell types such as
embryonic stem cells or induced pluripotent stem cells, MSCs
migrate and home to injured sites, acting both by regenerating
tissues and by secreting trophic factors and paracrine mediators.
MSCs have remarkable immunosuppressive properties secreting
cytokines and immunomodulatory substances.
MSCs secret neurotrophic and angiogenic factors
Delivering neurotrophic or angiogenic factors in the form of
protein or gene for therapy have no signicant effect. BMSCs
are effective for reversing various manifestations of experimental
MSCs secrete various cytokines with angiogenic and
neurosupportive effects. MSCs reside in the BM stromal fraction,
which provides the cellular microenvironment supporting hema-
topoiesis. MSCs are adherent and expandable in culture, which
makes it relatively easy to obtain a sufcient number of cells for
MSC therapy.
Human MSCs (hMSCs) produce 84 trophic factors in conditioned
medium and/or cell lysates versus basal medium.
Human umbilical
cord blood MSC treatment partially restore the neuronal degenera-
tion and nerve function of femoral nerve.
Human umbilical
cord-derived MSCs secrete VEGF, glial cell line-derived neurotrophic
factor (GDNF), and BDNF. Secretion of neurotrophic factors is
demonstrated before, during, and after neuronal differentiation.
Human umbilical cord-derived MSCs and BMSCs both had
measurable amounts of secreted neurotrophic factors. But in vivo
tests did not conrm the secretion of neurotrophic factors and the
antiapoptotic effects seen in vitro.
Dental pulp stem cells express various neurotrophic factors,
including BDNF, NGF, and GDNF.
The transplantation of cryopre-
served dental pulp stem cells attenuate sciatic nerve blood ow and
sciatic nerve conduction velocity the same as freshly isolated dental
pulp stem cells.
Similarly, adipose-derived stem cells differentiated
to glial-like cells also express a range of neurotrophic factors, namely
NGF, BDNF, GDNF, and neurotrophin 4. MSC transplantion into
an animal model of nerve injury show antiapoptosis in the dorsal
root ganglia.
Adipose tissue-derived stem cells isolated from the
ischemic limb of diabetic patients have less potent phenotypically
and functionally compared with control normal counterparts
without signs of limb ischemia.
Neuroprotective and neuroregenerative mechanisms
The secretion of neurotrophic factors by stem cells provides
neuroprotection and neuroregenerative effects. When trans-
planted into an animal model of Parkinsons disease, hMSCs
support sustained endogenous proliferation and maturation
of cells in the subventricular zone of rats. Additionally, hMSCs
exert a neuroprotective effect, decreasing the loss of dopami-
nergic neurons and increasing the levels of dopamine in the
animal models of Parkinsonsdisease.
These effects are
possibly accomplished through decreased caspase-3 activity.
hMSC-treated mice have a lower removal times than that injected
Figure 1. Pathogenesis of diabetic neuropathy.
Mesenchymal stem cells to treat diabetic neuropathy
JY Zhou et al
Cell Death Discovery (2016) e16055 Ofcial journal of the Cell Death Differentiation Association
with proteasome inhibitors and no hMSC transplantation.
planted hMSCs did not differentiate into a neural phenotype
protected against Purkinje cell loss.
These studies demonstrate that
MSCs not only protect against nerve damage but also help regenerate
damaged nerves and restore them to their preinjured state.
The secretion of neurotrophic factors by different populations
of stem cells suggests that no matter the source MSCs have the
ability to decrease and ameliorate the negative effects on injured
nerve bers, improving the function of the injured nerve. The
release of key neurotrophic factors, along with the neuroprotec-
tive and neuroregenerative effects of stem cells, make them ideal
candidates for arresting and possibly reversing the incapacitating
effects of DN.
MSC therapy may not be a standard treatment option for
all stages of DN because different stages of DN are marked by
different structural or functional changes. At present, MSC therapy
may be applied to those patients who suffer from intractable
symptoms, acute exacerbation, or combined diseases, such as
diabetic foot ulcers or critical limb ischemia. MSC therapies
targeting both vascular and neural elements are advantageous
in treating DN.
One recent meta-analysis shows that BMSC
transplantation ameliorates allodynia but not hyperalgesia unless
it is given during the rst 4 days after injury.
As shown in
Figure 2, stem cells can improve DN through two main pathways.
MSCs improve diabetic glycemic control
MSCs improve glycemic control, accompanied by improved renal
function and regeneration of normal βpancreatic islets.
cemia of MSC transplantation is a direct effect of differentiation to
cells capable of producing insulin (less likely) or an indirect effect of
secretion of immunomodulators, which prevent T cells from eliciting
pancreatic β-cell destruction, or other as yet unknown factors that
inuence insulin secretion or action. MSC differentiate into insulin-
producing cells, releasing insulin in a glucose-dependant manner
and improving diabetic symptoms in type 1 diabetic animal.
These insulin-producing cells express multiple genes related to the
development or function of pancreatic βcells.
In diabetic NOD
mice, the injection of MSC reduced the capacity of diabetogenic T cells
to inltrate pancreatic islets thus preventing β-cell destruction.
An additional cooperative action of MSCs on co-transplantation with
pancreatic islets results in improved graft morphology and improved
revascularization, indicating that possible trophic factors secreted by
MSCs are aiding islet engraftment.
Multiple intravenous infusions of
MSCs resulted in normalization of hyperglycemia, which remained
stable for 9 weeks after infusion, with lower serum levels of insulin and
C-peptide and reversed damaged pancreatic islets to near normal.
MSCs secret neurotrophic and angiogenic factors to ameliorate
MSCs offer a novel therapeutic option to treat DN. MSCs modulate
the central nervous system-injured environment and promote
repair as they secrete anti-inammatory, antiapoptotic molecules,
and trophic factors to support axonal growth, immunomodulation,
angiogenesis, remyelination, and protection from apoptotic cell
MSCs are known to support angiogenesis mostly through
a paracrine effect, which augments the microcirculation support-
ing peripheral nerves. This impaired vascular supply has been
implicated in the etiology of DN. Transplanted MSCs not only
directly differentiate into neurons and endothelial cells but also
secrete an increased concentrations of biologically active factors,
such as FGF, VEGF-A, and NGF,
which are central to nerve and
vascular tissue health. Adipose-derived MSC sheet, which secret
large amounts of several angiogenic growth factors in vitro, both
directly and indirectly accelerate diabetic wound healing.
BMSC transplantation increased the expression levels of FGF2
and VEGF, ameliorated sciatic nerve blood ow, prevented
the decreases in the capillary-to-muscle ratio and the neurola-
ment content, and improved motor nerve conduction velocity
in diabetic animals.
Despite these benets, however, motor
nerve conduction velocity and the increase in the levels of NGF
and neurotrophin 3 last for only 4 weeks.
Interestingly, when
it comes to neurotrophic factors, these two studies contradict
each other. In one study,
levels of NGF and neurotrophin 3, but
not VEGF or FGF2, increase in the animals that received BMSC
transplantation. In another study,
however, VEGF and FGF2, but
not NGF and neurotrophin 3, are found to increase in the animals
that received stem cell transplantation. More studies are needed
to understand the effects of MSCs on DN.
MSCs inhibit proinammation to improve diabetic peripheral
The therapeutic benet of MSCs in DN is now believed to be by
short-term (hours to days) paracrine and juxtacrine modulation of
immune responses rather than by long-term (days to months)
engraftment of MSCs to the injured site.
Subsequent improve-
ments in MSC cell preparations to generate anti-inammatory
MSC populations resulted in improvements in behavioral assays in
painful diabetic peripheral neuropathy, and mice treated with these
MSCs showed decreased serum concentrations of proinammatory
hMSCs reduce pain-like behaviors (mechanical allodynia
and thermal hyperalgesia) after transplanted in cerebral ventricle.
hMSCs have antinociceptive effect from day 10 after surgery
(6 days after cell injection). hMSCs reduce the mRNA expression
levels of interleukin-1βand neural β-galactosidase overactivation
in prefrontal cortex of spared nerve injury mice.
hMSCs reduce
mechanical allodynia and thermal hyperalgesia via tail vein
injection. An antinociceptive effect is measurable from day 11 after
surgery (7 days after cell injection). hMSCs mostly home in the spinal
cord and prefrontal cortex of neuropathic mice. Transplanted hMSCs
downregulate the expression levels of the mouse interleukin-1βand
interleukin-17 and upregulate the expression levels of interleukin-10
and the marker of alternatively activated macrophages CD106 in the
spinal cord of spared nerve injury mice.
MSCs improve diabetic cardiac autonomic neuropathy
MSC administration promoted density of sympathetic and para-
sympathetic nerves in the ventricular myocardium of diabetic rats,
increased the ratio of parasympathetic to sympathetic nerve
bers, and suppressed ventricular arrhythmia inducibility.
Figure 2. Mechanisms of the effect of stem cell transplantation on
diabetic neuropathy.
Mesenchymal stem cells to treat diabetic neuropathy
JY Zhou et al
Ofcial journal of the Cell Death Differentiation Association Cell Death Discovery (2016) e16055
MSCs regenerate axons and format myelin to ameliorate DN
The injected BMSCs into hindlimb muscles of streptozotocin-
induced diabetic rats restore motor and sensory nerve conduction
velocities to near-normal levels. The injected MSCs are priority and
durably engrafted in the sciatic nerves, and a fraction of the
engrafted MSCs are discriminatively localized near to vasa nervora
of sciatic nerves. MSCs increase the density of vasa nervora and
restores the ultrastructure of myelinated bers in nerves. MSCs also
upregulate the gene expression of multiple factors participating in
angiogenesis, neural function, and myelination in the MSC-injected
The nerve grafts that are prepared from poly (3-hydroxy-
butyrate-co-3-hydroxyhexanoate) with oriented nanober three-
dimensional surfaces aided to nerve regeneration, either used alone
or with hMSC. Poly (3-hydroxybutyrate-co-3-hydroxyhexanoate)
provided better nerve regeneration when used with hMSCs in
combination than alone and reached the same statistical treatment
effect in functional evaluation and electrophysiological evaluation
when compared with autografting.
The application of the use of MSCs to treat DN has been
extensively investigated in preclinical animal models in recent
years and the majority of reports indicate positive effects on DN.
Despite this, there are signicant challenges to be met for the
successful clinical translation of these studies from animal model
to the patients bedside. Although MSC therapies protect from
neurodegeneration and promote neuroregeneration, there appear
to be many obstacles to be overcome for clinical applications
(Figure 3). These are: (1) optimal dose of administration owing
to limited survival of transplanted cells, (2) safety for risk of
tumor formation, (3) route of transplantation for effectiveness,
(4) autologous or allogeneic approach, impairing potency of MSCs
from diabetes, (5) further mechanisms, and (6) clinical end points
for the efcacy of MSC therapy.
Even with the reported concerns over possible malignant
transformation above, worldwide clinical studies of both auto-
logous and allogeneic MSC administration have conrmed clinical
safety and initial efcacy. A search of the ClinicalTrials.Gov website
reveals that there are 612 open studies of MSC safety and efcacy
in the treatment of human diseases by the year 2016. In relation
to diabetes, there are 39 open clinical trials using MSCs to treat
type 1 diabetes, type 2 diabetes, or their associated complications.
Another issue that should be overcome for the MSC therapy is
to avoid the risk of tumor formation. Increased tumor formation
was observed in animals owing to the immune-suppressive
effect of MSCs especially with allogeneic transplants,
in vitro observations of sarcoma after culture of murine MSCs was
But one study indicated a tumor-suppressive activity of
MSCs after preactivation with tumour necrosis factor-α.
tumor formation in streptozotocin-induced diabetic mice trans-
planted with BMSCs was observed.
The high frequency of tumor
formation is accounted for by frequent chromosomal mutation
elicited by repeated passages of BMSCs (only four passages) in the
cell culture system. It may thus be conceivable that fresh BMSCs
without any passage in cell culture should be applied to MSC
therapy to prevent tumor formation.
Dose of administration
The number of cells delivered are very important; however, there
is still a lack of information as to the optimal cell doses that
provide preclinical and clinical efcacy. One study demonstrated
that hMSCs transplanted into animal model generated different
grafts depending on the cell dosing: low numbers of transplanted
hMSCs generated nestin-containing grafts, whereas higher
numbers of transplanted hMSCs generated considerable amounts
of grafts with astroglial markers.
The number of cells trans-
planted also raises questions about cell survival; one study
indicated that only 1.7% of total injected hMSCs survived.
Despite all of their benets, much research still needs to be carried
out to understand the homing capabilities of stem cells
and the
mechanism of action.
The optimal dose for stem cell transplan-
tation needs further characterization prior to being introduced
into clinical trials.
Route of administration
Methods for transportation of MSCs without affecting their
viability and efcacy are important along with issues related
to cryopreservation. Several modes of cell delivery (e.g., topical,
intraocular, and systemic) have been assessed in both preclinical
and clinical studies, and these studies have illustrated the
importance of administration route with the successful outcome.
Systemic delivery is attractive as this may result in benet for
multiple complications and has the potential to improve glycemic
control. Although an attractive option, the systemic delivery of
MSCs has some barriers, such as homing of these cells to tissues
of interest with high efciency and clinically meaningful engraft-
ment. More cells are required for injection owing to passive cell
entrapment within non-specic tissues,
and this can poten-
tially lead to unwanted effects and reduced efcacy of trans-
planted cells. Topical application may be a very relevant alternate
strategy for diabetic foot ulcers but this is approach can be limited
by localized vascular damage as a result of diabetes at the site of
administration. One approach is to implant cells repeatedly to
maintain their effects. At present, the duration of the benecial
effects of MSC therapy in DN is unknown.
Duration and degree of cell expansion
A major challenge is the large-scale production of MSCs under
GMP conditions and issues of MSC heterogeneity. The duration
and degree of cell expansion and culture has an impact on MSC
morphology, differentiation, viability, and migratory properties.
MSCs not only undergo phenotypic changes in culture and during
passage (size, morphology, and cell surface marker expression)
but also lose capacity for functional proliferation and differentia-
tion potential.
In addition, their ability for cytokine production
is altered.
Thus a delicate balance between culture expansion to
gain sufcient numbers of MSCs for therapeutic application and
long-term culture effects needs to be met. Tightly controlling the
microenvironment of MSCs is required. Detailed investigations of
how the microenvironment affects the immunosuppressive effects
of MSCs are still lacking and are required as cell-to-cell contact and
Figure 3. Challenges for clinical application of MSCs to treat diabetic
Mesenchymal stem cells to treat diabetic neuropathy
JY Zhou et al
Cell Death Discovery (2016) e16055 Ofcial journal of the Cell Death Differentiation Association
soluble factors are thought to be the key aspects of MSC-mediated
Autologous or allogeneic approach
The choice of an autologous or allogeneic approach is an important
consideration as the former may be limited by disease-induced
cell dysfunction and the latter by an immune response to the
transplanted cells. Historical opinions that the immunomodulatory
functions of MSCs results in immune privilege for allogeneic MSC
transplants are being challenged
with the recommendation
that the antidonor immune responses elicited by allogenic MSCs be
studied in more detail. The limitation of allogenic MSC therapy may
also be related to the gradual decrease in released neurotrophic
factors from transplanted cells that may sustain only 4 weeks or so
after transplantation.
Despite numerous studies on the transplantation of MSCs in animal
models and patients, insight into the exact mechanisms of action
underlying their benecial effect remains unclear. Adequate
preclinical animal models are required to accurately represent the
pathological long-term effects of diabetes on the host system. There
are limitations in the current rodent models of DN.
There is an
increased need for additional in vitro and in vivo studies to fully
describe in detail the mechanisms of MSC therapy.
DN frequently leads to foot ulcers and ultimately limb amputations
without effective clinical therapy. DN is characterized by reduced
vascularity in the peripheral nerves and deciency in angiogenic
and neurotrophic factors. Only delivering neurotrophic or angio-
genic factors for treatment in the form of protein or gene therapy is
very modest if not ineffective. MSCs have been highlighted as a new
emerging regenerative therapy owing to their multipotency for DN.
MSCs reverse manifestations of DN, repair tissue, and antihypergly-
cemia. MSCs also paracrinely secrete neurotrophic factors, angio-
genic factors, cytokines, and immunomodulatory substances to
ameliorate DN. Challenges in the clinical translation of MSC therapy
include safety, optimal dose of administration, optimal mode of cell
delivery, issues of MSC heterogeneity, clinically meaningful engraft-
ment, autologous or allogeneic approach, challenges with cell
manufacture, and further mechanisms.
BDNF, brain-derived nerve factor; BMSC, bone marrow-derived MSC;
DN, diabetic neuropathy; FGF2, broblast growth factor-2; GDNF,
glial cell line-derived neurotrophic factor; hMSC, human MSC; MSC,
mesenchymal stem cell; NGF, nerve growth factor; VEGF, vascular
endothelial growth factor.
This work was supported by a grant from the National Natural Science Foundation of
China (No. 81471040), the Chongqing Natural Science Foundation of China (No.
cstc2015jcyjBX0138), the Natural Science Foundation of Third Military Medical
University (No. 2012XJQ17), and Clinical research projects of Xinqiao Hospital, Third
Military Medical University (No. 2015YLC32).
JY Zhou and GS Qian wrote the manuscript; JY Zhou and Z Zhang prepared the
gures and organized the contents of the manuscript.
The authors declare no conict of interest.
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Mesenchymal stem cells to treat diabetic neuropathy
JY Zhou et al
Ofcial journal of the Cell Death Differentiation Association Cell Death Discovery (2016) e16055
... The administration of MSCs ameliorates the symptoms of diabetic neuropathy because of their multipotency. MSCs repair tissue, lower blood sugar concentration, and produce angiogenic factors, neurotrophic factors, exosomes, and cytokines to improve diabetic neuropathy [10,11]. The stromal cell-derived factor-1α (SDF-1α, CXCL12) chemokine and its receptor, CXC chemokine receptor 4 (CXCR4), play a critical role in mobilizing and recruiting MSCs. ...
... Type 1 diabetes triggers intrinsic functional dysfunction in endogenous bone marrow MSCs prior to neuropathogenesis [41]. Therefore, earlier therapeutic methods targeting the bone marrow niche can regulate bone marrow MSC functional dysfunction and delay the development of neuropathy [10]. ...
... MSCs accelerate peripheral nerve regeneration through direct generation of neurotrophic factors and indirect regulation of Schwann cell-specific pathways [55]. After transplantation with progenitor or stem cells, diabetic animals show improved nerve blood flow, nerve conduction velocity, intraepidermal nerve fiber density, and sensory diseases, with an elevation in myelin thickness [10,56,57]. The supernatant from cultured dental pulp stem cells increases the proliferation of Schwann cells and the generation of myelin-related proteins in Schwann cells, indicating that Schwann cells are the major target of cell transplantation in diabetic neuropathy [58]. ...
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The purpose of this study is to explore the effect and mechanism of neuritin overexpression in the bone marrow on peripheral neuropathy in type 2 diabetic (db/db) mice. We analyzed the impact of bone marrow neuritin overexpression on diabetic peripheral neuropathy and migration of bone marrow mesenchymal stem cells in db/db mice. Antagonists were used to inhibit the stromal cell-derived factor (SDF)-1α/C-X-C chemokine receptor type 4 (CXCR4)-phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in primary cultured bone marrow mesenchymal stem cells. Immunofluorescence, transmission electron microscopy, Oil Red O staining, and transwell migration assays were used. Bone marrow-specific overexpression of neuritin in db/db mice was successfully established. Overexpression of neuritin in the bone marrow ameliorated hyperglycemia, prevented diabetic peripheral neuropathy, protected the ultrastructure of the sciatic nerve and intra-epidermal nerve fiber density, and promoted Schwann cell proliferation and remyelination in the sciatic nerve. Moreover, it ameliorated fat accumulation, adipocyte number, and vascular and nerve densities; decreased glutamate content in serum and bone marrow; restored gradient SDF-1α contents between bone marrow, blood, and sciatic nerve; and promoted impaired diabetic bone marrow mesenchymal stem cell migration. Neuritin improves bone marrow mesenchymal stem cell migration via the SDF-1α/CXCR4-PI3K/Akt signaling pathway in vitro. Overexpression of neuritin in the bone marrow can locally ameliorate neuropathy in the bone marrow. This improves the migration capability of bone marrow mesenchymal stem cells and repairs diabetic peripheral neuropathy, at least partly by activating the PI3K/Akt pathway through the SDF-1α/CXCR4 axis.
... MSCs release different anti-inflammatory and antiapoptotic molecules, as well as fibroblast and vascular endothelial growth factors, which promote and induce remyelination and growth of damaged peripheral axons, as well as the growth of blood vessels responsible for the nutrition of nerve fibres. Mice treated with MSCs had lower levels of proinflammatory cytokines in serum, as shown in Fig. 6 [109]. They also affect cardiac autonomic neuropathy by increasing the ratio of parasympathetic to sympathetic nerve fibres and consequently reducing the onset of ventricular arrhythmia. ...
... MSCs promote angiogenesis, improve vascularization of the foot, as well as the proliferation of endothelial cells and fibroblasts, mostly by the release of different growth factors, alterations of various signalling pathways and involvement of different microRNAs [111]. and release insulin, which was proven in animals with T1D [109]. Recently, the topical and intravenous use of MSCs has been investigated in patients with diabetic foot ulcers and peripheral arterial disease. ...
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Background: Neuropathy is among the most often reported consequences of diabetes and the biggest cause of morbidity and mortality in people suffering from this life-long disease. Although different therapeutic methods are available for diabetic neuropathy, it is still the leading cause of limb amputations, and it significantly decreases patients’ quality of life. Aim: This study investigates potential novel therapeutic options that could ameliorate symptoms of DN. Methodology: Research and review papers from the last 10 years were taken into consideration. Results: There are various traditional drugs and non-pharmacological methods used to treat this health condition. However, the research in the area of pathogenic-oriented drugs in the treatment of DN showed no recent breakthroughs, mostly due to the limited evidence about their effectiveness and safety obtained through clinical trials. Consequently, there is an urgent demand for the development of novel therapeutic options for diabetic neuropathy. Conclusion: Some of the latest novel diagnostic methods for diagnosing diabetic neuropathy are discussed as well as the new therapeutic approaches, such as the fusion of neuronal cells with stem cells, targeting gene delivery and novel drugs.
... The robust potential of stem cells to differentiate into specific types of cells and regenerate tissues and body organs has been proven in several studies [19]. Stem cell therapy has been believed to be a promising regenerative therapy for different neurological diseases including DPN because of its potency of regeneration and paracrine secretion of several factors such as angiogenic and neurotrophic factors (Refer to Table 1) [20]. In this article, we will discuss the possibility and future of cell therapy for the cure of progressive DPN. ...
... Meanwhile, MSCs are stupendous candidates for treating DPN. MSCs are identified by several markers such as CD54/CD102, CD166, CD73, CD90, CD44, and CD105 [20]. MSCs can differentiate into mesodermal cells in origin, such as bone, cartilage, and adipose tissue [132]. ...
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Diabetic polyneuropathy (DPN) is the most frequent, although neglected, complication of long-term diabetes. Nearly 30% of hospitalized and 20% of community-dwelling patients with diabetes suffer from DPN; the incidence rate is approximately 2% annually. To date, there has been no curable therapy for DPN. Under these circumstances, cell therapy may be a vital candidate for the treatment of DPN. The epidemiology, classification, and treatment options for DPN are disclosed in the current review. Cell-based therapies using bone marrow-derived cells, embryonic stem cells, pluripotent stem cells, endothelial progenitor cells, mesenchymal stem cells, or dental pulp stem cells are our primary concern, which may be a useful treatment option to ease or to stop the progression of DPN. The importance of cryotherapies for treating DPN has been observed in several studies. These findings may help for the future researchers to establish more focused, accurate, effective, alternative, and safe therapy to reduce DPN. Cell-based therapy might be a permanent solution in the treatment and management of diabetes-induced neuropathy.
... DN is one of the most common long-term diabetes-related health problems. It affects more than 66% of type I diabetes patients and more than 59% of type II diabetes patients worldwide [1,2]. The most common symptoms are pain, burning, numbness, tingling and cramp [3]. ...
... The use of stem cell applications is a new approach in neuropathies. It is known that mesenchymal stem cells (MSCs) are promising treatments for DN due to their ability to secrete trophic factors [1,14,15]. Human MSCs produce 84 trophic factors in in vitro [16]. Transplanted MSCs synthesize many trophic factors that are deficient in neuropathies. ...
Diabetic neuropathy (DN) is the most common degenerative complication associated with Diabetes Mellitus. Despite widespread awareness about DN, the only effective treatments are blood glucose control and pain management. The aim of the current study was to determine the effect of intramuscular adipose-derived mesenchymal stem cell (AMSC) transplantation on sciatic nerves in DN using EMG and histological analyses. A total of 27 mice were randomly divided into three groups: control group, DN group and AMSC group. In EMG, CMAP amplitude in the sciatic nerves was lower, but distal latency was higher in the DN group compared with the control group. CMAP amplitude in the sciatic nerves was higher in the AMSC group compared with the DN group. Distal latency in the sciatic nerve was lower in the AMSC group compared with the DN group. Histologic examination of the tissues in the animals treated with AMSC showed a remarkable improvement in microscopic morphology. Fluorescence microscopy analyses demonstrated that intramuscularly transplanted AMSC was selectively localized in the sciatic nerves. Transplantation of AMSC increased protein expression of S100, cdk2, NGF and DHH, all of which, interfered with DN onset in sciatic nerves. The findings of the present study suggest that AMSC transplantation improved DN through a signal-regulatory effect on Schwann cells, neurotrophic actions and restoration of myelination. Keywords: Diabetic neuropathy; adipose-derived mesenchymal stem cell; cdk2; dhh; emg; ngf; s100; schwann cell.
... Replacement of cells that were previously injured has an impactful role along with delivering trophic factors [12]. MSCs have been shown to be capable of self-renewing and have the potential to differentiate into variable cell types including neurons, adipocytes, osteoblasts, and more [13]. As of now, there is no definite treatment of NP syndrome with concurrent promotion of nervous system repair. ...
... Generating anti-inflammatory MSCs has been shown to alleviate diabetic neuropathy pain. In a mice treatment module, MSC therapy has been shown to reduce proinflammatory cytokine concentrations in the mice's serum [13]. Prior to and after receiving MSC therapy, the mice were evaluated for painful diabetic neuropathy through two established behavioural assays [16]. ...
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Pain management has always been a challenging issue, which is why it has been a major focus of many rigorous studies. Chronic pain which typically lasts for more than three months is prevalent at an astounding rate of 11% to 19% of the adult population. Pain management techniques have gone through major advances in the last decade with no major improvement in the quality of life in affected populations. Recently there has been growing interest in the utilization of stem cells for pain management. Advancement of stem cell therapy has been noted for the past few years and is now being used in human clinical trials. Stem cell therapy has shown promising results in the management of neuropathic, discogenic back, osteoarthritis, and musculoskeletal pain. In this article, we will discuss the role of stem cells in the pain management of the aforementioned conditions, along with the mechanism, adverse effects, and risks of stem cell therapy.
... The COVID milieu since 2019 has driven healthcare professionals to emphasize the matter of management and nursing of patients suffering from diabetic neuropathy since DM patients are prone to have compromised immunity and disturbed microenvironment (49). Typically, patients suffering from diabetic neuropathy show decreased peripheral nerve vascularity and a deficiency of angiogenic and neurotrophic factors, which may account for the pathogenesis of neuropathies (50,51). Recently, the therapeutic effects of DPSCs in diabetic neuropathy have become recognized by many researchers, which raised controversies regarding the optimal application method of DPSCs. ...
Full-text available
Peripheral nerve diseases are significantly correlated with severe fractures or trauma and surgeries, leading to poor life quality and impairment of physical and mental health. Human dental pulp stem cells (DPSCs) are neural crest stem cells with a strong multi-directional differentiation potential and proliferation capacity that provide a novel cell source for nerve regeneration. DPSCs are easily extracted from dental pulp tissue of human permanent or deciduous teeth. DPSCs can express neurotrophic and immunomodulatory factors and, subsequently, induce blood vessel formation and nerve regeneration. Therefore, DPSCs yield valuable therapeutic potential in the management of peripheral neuropathies. With the purpose of summarizing the advances in DPSCs and their potential applications in peripheral neuropathies, this article reviews the biological characteristics of DPSCs in association with the mechanisms of peripheral nerve regeneration.
... Interestingly, it has been demonstrated that MSCs could directly suppress T-cells activation/proliferation while inducing its apoptosis by expressing nitric oxide (NO), indoleamine 2,3, dioxygenase (IDO), programmed death-ligand 1 (PD-L1), or Fas ligand. Hence, the starting hypothesis is that MSCs hypoglycemic effect could be considered as an indirect effect of secretion of immunomodulators, which prevent T-cells from eliciting pancreatic β-cell destruction in T1DM (Zhou et al., 2016;Sordia et al., 2017). Additionally, MSCs transplantation was found to alleviated tissue inflammatory infiltration of lymphocytes and macrophages by lowering expression of IL-1β, IL-6, IL-8, MCP-1, TGF-β, TNF-α, and other pro-inflammatory cytokines in diabetic rats (Chandravanshi and Bhonde, 2017;Hamza et al., 2017). ...
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Since Type 1 diabetes (T1DM) occurs when β-cells mass is reduced to less than 20% of the normal level due to autoimmune destruction of cells resulting in the inability to secrete insulin, preservation or replenishment of the functional β-cells mass has become a major therapeutic focus for this diabetic type treatment. Thus, this 4-week work plan was designed to determine which mesenchymal stem cells (MSCs) type is more appropriate to alleviate pancreatic hazards resulting from diabetes induction; via tracking a comparative study between MSCs derived from adipose tissue (AD-MSCs) and from bone marrow (BM-MSCs) in management of T1DM considering their immunomodulatory, anti-apoptotic and antioxidative roles. Rats were divided randomly into 4 groups; control, STZ-diabetic (D), D+AD-MSCs, and D+BM-MSCs groups. Both stem cells types in this study were allogenic. Herein, both oxidative stress and antioxidant markers were evaluated using colorimetric analysis, while inflammatory, immune and apoptotic markers were assessed through flow cytometric analysis. Results showed that diabetic rats treated with either AD-MSCs or BM-MSCs exhibited marked pancreatic antioxidant and anti-inflammatory activities that were able to initiate pancreatic immunomodulation and reducing β-cells apoptotic death, thus, help to restore their normal insulin secretion and hypoglycemic abilities. However, AD-MSCs injection was shown to be superior as a pancreatic regenerative tool in overcoming diabetes; owing to their marked antioxidant, anti-inflammatory, immunomodulatory, and anti-apoptotic characteristics over BM-MSCs treatment. © 2022 Centro Regional de Invest. Cientif. y Tecn.. All rights reserved.
... The experimental design of the in-vivo DPN study is represented in Fig. 5A. Stem cells have been investigated for the treatment of DPN, however, the translation of the therapy from bench to bed side has been difficult due to certain underlying disadvantages such as ideal route and dose of administration, concern of tumor development and low cell retention capacity [54]. Moreover, there are growing evidences that the therapeutic effect of these stem cells is due to secretion of paracrine factors such as exosomes. ...
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Diabetic peripheral neuropathy (DPN) is a long-term complication associated with nerve dysfunction and uncontrolled hyperglycemia. In spite of new drug discoveries, development of effective therapy is much needed to cure DPN. Here, we have developed a combinatorial approach to provide biochemical and electrical cues, considered to be important for nerve regeneration. Exosomes derived from bone marrow mesenchymal stromal cells (BMSCs) were fused with polypyrrole nanoparticles (PpyNps) containing liposomes to deliver both the cues in a single delivery vehicle. We developed DPN rat model and injected intramuscularly the fused exosomal system to understand its long-term therapeutic effect. We found that the fused system along with electrical stimulation normalized the nerve conduction velocity (57.60 ± 0.45 m/s) and compound muscle action potential (16.96 ± 0.73 mV) similar to healthy control (58.53 ± 1.10 m/s; 18.19 ± 1.45 mV). Gastrocnemius muscle morphology, muscle mass, and integrity were recovered after treatment. Interestingly, we also observed paracrine effect of delivered exosomes in controlling hyperglycemia and loss in body weight and also showed attenuation of damage to the tissues such as the pancreas, kidney, and liver. This work provides a promising effective treatment and also contribute cutting edge therapeutic approach for the treatment of DPN.
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With the global prevalence of diabetes mellitus over recent decades, more patients suffered from various diabetic complications, including diabetic ocular surface diseases that may seriously affect the quality of life and even vision sight. The major diabetic ocular surface diseases include diabetic keratopathy and dry eye. Diabetic keratopathy is characterized with the delayed corneal epithelial wound healing, reduced corneal nerve density, decreased corneal sensation and feeling of burning or dryness. Diabetic dry eye is manifested as the reduction of tear secretion accompanied with the ocular discomfort. The early clinical symptoms include dry eye and corneal nerve degeneration, suggesting the early diagnosis should be focused on the examination of confocal microscopy and dry eye symptoms. The pathogenesis of diabetic keratopathy involves the accumulation of advanced glycation end-products, impaired neurotrophic innervations and limbal stem cell function, and dysregulated growth factor signaling, and inflammation alterations. Diabetic dry eye may be associated with the abnormal mitochondrial metabolism of lacrimal gland caused by the overactivation of sympathetic nervous system. Considering the important roles of the dense innervations in the homeostatic maintenance of cornea and lacrimal gland, further studies on the neuroepithelial and neuroimmune interactions will reveal the predominant pathogenic mechanisms and develop the targeting intervention strategies of diabetic ocular surface complications.
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Introduction: Dental pulp stem cells (DPSCs) are mesenchymal stem cells located in dental pulp and are thought to be a potential source for cell therapy since DPSCs can be easily obtained from teeth extracted for orthodontic reasons. Obtained DPSCs can be cryopreserved until necessary and thawed and expanded when needed. The aim of this study is to evaluate the therapeutic potential of DPSC transplantation for diabetic polyneuropathy. Methods: DPSCs isolated from the dental pulp of extracted incisors of Sprague-Dawley rats were partly frozen in a -80 °C freezer for 6 months. Cultured DPSCs were transplanted into the unilateral hindlimb skeletal muscles 8 weeks after streptozotocine injection and the effects of DPSC transplantation were evaluated 4 weeks after the transplantation. Results: Transplantation of DPSCs significantly improved the impaired sciatic nerve blood flow, sciatic motor/sensory nerve conduction velocity, capillary number to muscle fiber ratio and intra-epidermal nerve fiber density in the transplanted side of diabetic rats. Cryopreservation of DPSCs did not impair their proliferative or differential ability. The transplantation of cryopreserved DPSCs ameliorated sciatic nerve blood flow and sciatic nerve conduction velocity as well as freshly isolated DPSCs. Conclusions: We demonstrated the effectiveness of DPSC transplantation for diabetic polyneuropathy even when using cryopreserved DPSCs, suggesting that the transplantation of DPSCs could be a promising tool for the treatment of diabetic neuropathy.
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One of the most common complications of diabetes is diabetic foot ulcer. Diabetic ulcers do not heal easily due to diabetic neuropathy and reduced blood flow, and nonhealing ulcers may progress to gangrene, which necessitates amputation of the patient's foot. This study attempted to develop a new cell-based therapy for nonhealing diabetic ulcers using a full-thickness skin defect in a rat model of type 2 diabetes and obesity. Allogeneic adipose-derived stem cells (ASCs) were harvested from the inguinal fat of normal rats, and ASC sheets were created using cell sheet technology and transplanted into full-thickness skin defects in Zucker diabetic fatty rats. The results indicate that the transplantation of ASC sheets combined with artificial skin accelerated wound healing and vascularization, with significant differences observed 2 weeks after treatment. The ASC sheets secreted large amounts of several angiogenic growth factors in vitro, and transplanted ASCs were observed in perivascular regions and incorporated into the newly constructed vessel structures in vivo. These results suggest that ASC sheets accelerate wound healing both directly and indirectly in this diabetic wound-healing model. In conclusion, allogeneic ASC sheets exhibit potential as a new therapeutic strategy for the treatment of diabetic ulcers.
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Recent evidence has suggested that diabetic neuropathy (DN) is pathophysiologically related to both impaired angiogenesis and a deficiency of neurotrophic factors in the nerves. It is widely known that vascular and neural growth are intimately associated. Mesenchymal stem cells (MSCs) promote angiogenesis in ischemic diseases and have neuroprotective effects, particularly on Schwann cells. Accordingly, we investigated whether DN could be improved by local transplantation of MSCs by augmenting angiogenesis and neural regeneration such as remyelination. In sciatic nerves of streptozotocin (STZ)-induced diabetic rats, motor and sensory nerve conduction velocities (NCVs) and capillary density were reduced, and axonal atrophy and demyelination were observed. After injection of bone marrow-derived MSCs (BM-MSCs) into hindlimb muscles, NCVs were restored to near-normal levels. Histological examination demonstrated that injected MSCs were preferentially and durably engrafted in the sciatic nerves, and a portion of the engrafted MSCs were distinctively localized close to vasa nervora of sciatic nerves. Furthermore, vasa nervora increased in density, and ultrastructure of myelinated fibers in nerves were observed to be restored. Real-time RT-PCR experiments showed that gene expression of multiple factors involved in angiogenesis, neural function, and myelination were increased in the MSC-injected nerves. These findings suggest that MSC transplantation improved DN through direct peripheral nerve angiogenesis, neurotrophic effects, and restoration of myelination.
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Adipose tissue is an abundant source of autologous adult stem cells that may bring new therapeutic perspectives on the treatment of diabetes and its complications. It is unclear whether adipose tissue‐derived stromal cells (ASCs) of diabetic patients, constantly influenced by hyperglycaemia, have the same properties as non‐diabetic controls. As an alternative source of ASCs, adipose tissue from distal limbs of diabetic patients with critical ischemia was isolated. ASCs were characterized in terms of cell surface markers, multilineage differentiation and the expression of vascular endothelial growth factor (VEGFA), chemokine‐related genes and compared with non‐diabetic controls. Flow cytometry analysis confirmed mesenchymal phenotypes in both diabetic and non‐diabetic ASCs. Nevertheless, 40% of diabetic and 20% of non‐diabetic ASC samples displayed high expressions of fibroblast marker, which inversely correlated with the expression of CD105. In diabetic patients, significantly decreased expression of VEGFA and chemokine receptor CXCR4 was found in fibroblast‐positive ASCs, compared with their fibroblast‐negative counterparts. Reduced osteogenic differentiation and the downregulation of chemokine CXCL12 were found in fibroblast‐negative diabetic ASCs. Both diabetic and non‐diabetic ASCs were differentiated into adipocytes and chondrocytes and did not reveal islet‐like cell differentiation. According to this study, adipose tissue from distal limbs of diabetic patients is not satisfactory as an autologous ASC source. Copyright © 2014 John Wiley & Sons, Ltd. SIGNIFICANCE OF THE STUDY Hyperglycaemic milieu as well as other metabolic disorders linked to diabetes may have an influence on endogenous stem cell properties. The present study investigated the feasibility of autologous stem cell therapy in diabetic patients. ASCs isolated from the ischemic limb of diabetic patients were found to be less potent when compared phenotypically and functionally to control non‐diabetic counterparts with no signs of limb ischemia. High expression of fibroblast markers associated with reduced expression of VEGFA as well as reduced osteogenic differentiation may have an impact on the effectiveness of autologous cell therapies in diabetic patients.
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Abstract This study is designed to evaluate the treatment effect of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) and human mesenchymal stem cells (hMSC) on axonal regeneration in experimental rat sciatic nerve damage, and compare the results of this modality with autologous nerve grafting. In Spraque-Dawley albino rats, 10mm long experimental nerve gaps were created. Three groups were constituted, the gap was repaired with autologous nerve graft (autograft group), PHBHHx nerve graft alone (PHBHHx alone group) and PHBHHx nerve graft with hMSCs inside (PHBHHx with hMSC group), respectively. The results were evaluated with functional recovery, electrophysiological evaluation, and histological evaluation either with light microscopy and transmission electron microscopy for axonal regeneration and myelin formation. In functional evaluation, autograft and PHBHHx with hMSC groups showed functional improvement with time, whereas PHBHHx alone group did not. Electrophysiological evaluation showed better results in autograft and PHBHHx with hMSC groups when compared to PHBHHx alone group. There was no statistical difference between autograft and PHBHHx with hMSC groups. Histological evaluation showed regenerated axons in each group. Autograft group was better than the others, and PHBHHx with hMSC group was better than PHBHHx alone group both for axonal regeneration and myelin formation. This study showed that the nerve grafts which were prepared from PHBHHx with oriented nanofiber three dimensional surfaces aided to nerve regeneration, either used alone or with hMSC. PHBHHx provided better nerve regeneration when used with hMSCs inside than alone, and reached the same statistical treatment effect in functional evaluation and electrophysiological evaluation when compared to autografting.
Stem cell transplantation has been considered as a possible therapeutic method for neuropathic pain. However, no quantitative data synthesis of a stem cell therapy for neuropathic pain exists. Therefore, the present systematic review and meta-analysis, assessed the efficacy of bone marrow mesenchymal stem cell (BMMSC) transplantation on alleviating pain symptoms in animal models of neuropathic pain. In the present meta-analysis, controlled animal studies assessing the effect of administrating BMMSC on neuropathic pain were included through an extensive literature search of online databases. After collecting data, effect sizes were computed and the standardized mean difference (SMD) with 95% confidence interval (CI) was entered in all analyses. Random effects models were used for data analysis. Sensitivity and subgroup analyses were performed to investigate expected or measured heterogeneity. Finally, 14 study were included. The analyses showed that BMMSC transplantation lead to significant improvement on allodynia (SMD=2.06, 95% CI=1.09-3.03, I2=99.7%; p<0.001). The type of neuropathy (p=0.036), time between injury and intervention (p=0.02) and the number of transplanted cells (p=0.023) influence the improvement of allodynia after BMMSC transplantation. BMMSC transplantation have no effect on hyperalgesia (SMD=0.3, 95% CI=-1.09-1.68, I2=100%; p<0.001) unless it is transplanted during the first four days after injury (p=0.02). The present systematic review with meta-analyses suggests that BMMSC transplantation improves allodynia but does not have any significant effect on hyperalgesia unless it is given during the first four days after injury. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Neuropathy is observed in 50% of diabetic patients with diabetic foot. This study attempted to explore the potential role of human mesenchymal stem cells-umbilical cord blood (hMSCs-UC) in femoral nerve (FN) neuropathy. The model rats were established by one time administration of streptozotocin and empyrosis on the dorsal hind foot. At 3d, 7d, 14d after treatment with hMSCs-UC or saline through left femoral artery, the serum NGF was examined by ELISA; NF-200 expression in FN was evaluated by immunohistochemistry; the diameter and roundness of FN, the ratio of capillary and muscular fiber of gastrocnemius were calculated under light microscope; and neuronal degenerations, such as demyelization, axonal atrophy, and loose arrangement of nerve fibers, were observed by electronic microscope. The results showed that, in hMSCs-UC-treated model rats, serum NGF was increased with higher positive rate of NF-200. Although the difference in FN diameters was not established among groups, improvement of roundness of FN was confirmed with increase in the numbers of capillary in FN-innervated gastrocnemius; additionally, degenerative neuropathy was significantly improved. Importantly, the functional study of electroneurogram (ENG) showed that, slowed conduction of FN in model rats was significantly restored by hMSCs-CU treatment. These data suggested that hMSCs-UC-treatment partially reverse the neuronal degeneration and nerve function of FN, which might be contributed by the upregulation of NGF with dramatic angiogenesis in FN-innervated gastrocnemius, consequently reversing neuronal structure and function, preventing or curing foot ulceration. Copyright © 2015. Published by Elsevier Ireland Ltd.
BACKGROUND Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications. METHODS A total of 1441 patients with IDDM -- 726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. RESULTS In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of ≥ 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of ≥ 300 mg per 24 hours) by 54 percent (95 percent confidence interval, 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. CONCLUSIONS Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.