Repair of full-thickness tendon injury using connective tissue progenitors efficiently derived from human embryonic stem cells and fetal tissues.
ABSTRACT The use of stem cells for tissue engineering (TE) encourages scientists to design new platforms in the field of regenerative and reconstructive medicine. Human embryonic stem cells (hESC) have been proposed to be an important cell source for cell-based TE applications as well as an exciting tool for investigating the fundamentals of human development. Here, we describe the efficient derivation of connective tissue progenitors (CTPs) from hESC lines and fetal tissues. The CTPs were significantly expanded and induced to generate tendon tissues in vitro, with ultrastructural characteristics and biomechanical properties typical of mature tendons. We describe a simple method for engineering tendon grafts that can successfully repair injured Achilles tendons and restore the ankle joint extension movement in mice. We also show the CTP's ability to differentiate into bone, cartilage, and fat both in vitro and in vivo. This study offers evidence for the possibility of using stem cell-derived engineered grafts to replace missing tissues, and sets a basic platform for future cell-based TE applications in the fields of orthopedics and reconstructive surgery.
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ABSTRACT: Tendon is a strong connective tissue that transduces muscle-generated forces into skeletal motion. In fulfilling this role, tendons are subjected to repeated mechanical loading and high stress, which may result in injury. Tissue engineering with stem cells offers the potential to replace injured/damaged tissue with healthy, new living tissue. Critical to tendon tissue engineering is the induction and guidance of stem cells towards the tendon phenotype. Typical strategies have relied on adult tissue homeostatic and healing factors to influence stem cell differentiation, but have yet to achieve tissue regeneration. A novel paradigm is to use embryonic developmental factors as cues to promote tendon regeneration. Embryonic tendon progenitor cell differentiation in vivo is regulated by a combination of mechanical and chemical factors. We propose that these cues will guide stem cells to recapitulate critical aspects of tenogenesis and effectively direct the cells to differentiate and regenerate new tendon. Here, we review recent efforts to identify mechanical and chemical factors of embryonic tendon development to guide stem/progenitor cell differentiation toward new tendon formation, and discuss the role this work may have in the future of tendon tissue engineering.Journal of biomechanics 01/2014; · 2.66 Impact Factor
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ABSTRACT: Tissue engineering and regenerative medicine (TERM) has caused a revolution in present and future trends of medicine and surgery. In different tissues, advanced TERM approaches bring new therapeutic possibilities in general population as well as in young patients and high-level athletes, improving restoration of biological functions and rehabilitation. The mainstream components required to obtain a functional regeneration of tissues may include biodegradable scaffolds, drugs or growth factors and different cell types (either autologous or heterologous) that can be cultured in bioreactor systems (in vitro) prior to implantation into the patient. Particularly in the ankle, which is subject to many different injuries (e.g. acute, chronic, traumatic and degenerative), there is still no definitive and feasible answer to 'conventional' methods. This review aims to provide current concepts of TERM applications to ankle injuries under preclinical and/or clinical research applied to skin, tendon, bone and cartilage problems. A particular attention has been given to biomaterial design and scaffold processing with potential use in osteochondral ankle lesions.Journal of The Royal Society Interface 01/2014; 11(92):20130784. · 4.91 Impact Factor
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ABSTRACT: Tendon injuries are prevalent and problematic, especially among young and otherwise healthy individuals. The inherently slow innate healing process combined with the inevitable scar tissue formation compromise functional recovery, imposing the need for the development of therapeutic strategies. The limited number of low activity/reparative capacity tendon-resident cells has directed substantial research efforts towards the exploration of the therapeutic potential of various stem cells in tendon injuries and pathophysiologies. Severe injuries require the use of a stem cell carrier to enable cell localisation at the defect site. The present study describes advancements that injectable carriers, tissue grafts, anisotropically orientated biomaterials, and cell-sheets have achieved in preclinical models as stem cell carriers for tendon repair.Stem Cell Research & Therapy 03/2014; 5(38). · 3.65 Impact Factor
Tissue Eng Part A. 2010 Oct;16(10):3119-37.
Repair of full-thickness tendon injury using connective tissue progenitors efficiently
derived from human embryonic stem cells and fetal tissues.
Cohen S, Leshansky L, Zussman E, Burman M, Srouji S, Livne E, Abramov N, Itskovitz-
Sohnis and Forman Families Center for Stem Cell and Tissue Regeneration Research,
Faculty of Medicine, Technion, Haifa, Israel.
The use of stem cells for tissue engineering (TE) encourages scientists to design new
platforms in the field of regenerative and reconstructive medicine. Human embryonic stem
cells (hESC) have been proposed to be an important cell source for cell-based TE
applications as well as an exciting tool for investigating the fundamentals of human
development. Here, we describe the efficient derivation of connective tissue progenitors
(CTPs) from hESC lines and fetal tissues. The CTPs were significantly expanded and
induced to generate tendon tissues in vitro, with ultrastructural characteristics and
biomechanical properties typical of mature tendons. We describe a simple method for
engineering tendon grafts that can successfully repair injured Achilles tendons and
restore the ankle joint extension movement in mice. We also show the CTP's ability to
differentiate into bone, cartilage, and fat both in vitro and in vivo. This study offers
evidence for the possibility of using stem cell-derived engineered grafts to replace
missing tissues, and sets a basic platform for future cell-based TE applications in the
fields of orthopedics and reconstructive surgery.
PMID: 20486794 [PubMed - in process]
Int J Clin Exp Med. 2010 Sep 7;3(4):248-69.
Bone marrow and umbilical cord blood human mesenchymal stem cells: state of the art.
Malgieri A, Kantzari E, Patrizi MP, Gambardella S.
Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in all tissues, as
part of the perivascular population. As multipotent cells, MSCs can differentiate into
different tissues originating from mesoderm ranging from bone and cartilage, to cardiac
muscle. MSCs are an excellent candidate for cell therapy because they are easily
accessible, their isolation is straightforward, they can be bio-preserved with minimal loss
of potency, and they have shown no adverse reactions to allogeneic versus autologous
MSCs transplants. Therefore, MSCs are being explored to regenerate damaged tissue and
treat inflammation, resulting from cardiovascular disease and myo-cardial infarction (MI),
brain and spinal cord injury, stroke, diabetes, cartilage and bone injury, Crohn's disease
and graft versus host disease (GvHD). Most of the application and clinical trials involve
MSCs from bone marrow (BMMSCs). Transplantation of MSCs from bone marrow is
considered safe and has been widely tested in clinical trials of cardiovascular,
neurological, and immunological disease with encouraging results. There are examples of
MSCs utilization in the repair of kidney, muscle and lung. The cells were also found to
promote angiogenesis, and were used in chronic skin wound treatment. Recent studies
involve also mesenchymal stem cell transplant from umbilical cord (UCMSCt). One of
these demonstrate that UCMSCt may improve symptoms and biochemical values in
patients with severe refractory systemic lupus erythematosus (SLE), and therefore this
source of MSCs need deeper studies and require more attention. However, also if there are
79 registered clinical trial sites for evaluating MSC therapy throughout the world, it is still
a long way to go before using these cells as a routinely applied therapy in clinics.
PMID: 21072260 [PubMed - in process]
Am J Sports Med. 2010 Sep;38(9):1857-69. Epub 2010 May 27.
Repair of chronic osteochondral defects using predifferentiated mesenchymal stem cells
in an ovine model.
Zscharnack M, Hepp P, Richter R, Aigner T, Schulz R, Somerson J, Josten C, Bader A,
BACKGROUND: The use of mesenchymal stem cells (MSCs) to treat osteochondral
defects caused by sports injuries or disease is of particular interest. However, there is a
lack of studies in large-animal models examining the benefits of chondrogenic
predifferentiation in vitro for repair of chronic osteochondral defects.
HYPOTHESIS: Chondrogenic in vitro predifferentiation of autologous MSCs embedded in a
collagen I hydrogel currently in clinical trial use for matrix-associated autologous
chondrocyte transplantation facilitates the regeneration of a chronic osteochondral defect
in an ovine stifle joint.
STUDY DESIGN: Controlled laboratory study.
METHODS: The optimal predifferentiation period of ovine MSCs within the type I collagen
hydrogel in vitro was defined by assessment of several cellular and molecular biological
parameters. For the animal study, osteochondral lesions (diameter 7 mm) were created at
the medial femoral condyles of the hind legs in 10 merino sheep. To achieve a chronic
defect model, implantation of the ovine MSCs/hydrogel constructs was not performed until
6 weeks after defect creation. The 40 defects were divided into 4 treatment groups: (1)
chondrogenically predifferentiated ovine MSC/hydrogel constructs (preMSC-gels), (2)
undifferentiated ovine MSC/hydrogel constructs (unMSC-gels), (3) cell-free collagen
hydrogels (CF-gels), and (4) untreated controls (UCs). Evaluation followed after 6 months.
RESULTS: With regard to proteoglycan content, cell count, gel contraction, apoptosis,
compressive properties, and progress of chondrogenic differentiation, a differentiation
period of 14 days in vitro was considered optimal. After 6 months in vivo, the defects
treated with preMSC-gels showed significantly better histologic scores with morphologic
characteristics of hyaline cartilage such as columnarization and presence of collagen type
CONCLUSION: Matrix-associated autologous chondrocyte transplantation with
predifferentiated MSCs may be a promising approach for repair of focal, chronic
CLINICAL RELEVANCE: The results suggest an encouraging method for future treatment
of focal osteochondral defects to prevent progression to osteoarthritis.
PMID: 20508078 [PubMed - in process]
Orthopedics. 2010 Sep 7;33(9):661. doi: 10.3928/01477447-20100722-31.
Allograft alternatives: bone substitutes and beyond.
Excessive wear debris, deep infection, periprosthetic fracture, and other causes can lead
to bone loss associated with total joint replacements. When performing revisions,
surgeons are often preoccupied by the failed implant and the method of replacement, and
neglect an opportunity to replenish lost bone. Thus, when formulating a plan for revision
total joint replacement, the surgeon should consider not only the hardware that should be
used, but also ways in which lost bone could be restored. Autograft bone provides the
best source for osteoprogenitor cells, growth factors, and a scaffold. However, autograft is
limited in supply, and is generally associated with another incision, dissection, and
accompanying morbidity. Osteoconductive bone void fillers such as morselized
cancellous allograft bone, polymeric scaffolds, and biodegradable ceramics each have
their merits and deficiencies; however, all of these materials function as a scaffold only,
without the ability to induce bone formation. Osteoinductive growth factors are essential
to bone growth and remodeling; however, exogenous growth factors are expensive, are
given in large nonphysiological doses, may yield unpredictable clinical results, and may
have significant adverse effects. Demineralized bone matrix contains a scaffold and
variable amounts of several growth factors. Recently, the use of mesenchymal stem cells
and osteoprogenitors, together with a suitable scaffold carrier has gained increasing
popularity. With the addition of appropriate growth factors, this combination can provide
all the necessary components for osteogenesis. Future basic and clinical research will
define the indications and outcomes for new combination products for reconstruction of
lost bone associated with revision total joint replacement.
Copyright 2010, SLACK Incorporated.
PMID: 20839690 [PubMed - in process]
J Biomed Mater Res A. 2010 Aug 19. [Epub ahead of print]
Cartilage regeneration by bone marrow cells-seeded scaffolds.
Wegener B, Schrimpf FM, Bergschmidt P, Pietschmann MF, Utzschneider S, Milz S,
Jansson V, Müller PE.
Different approaches exist for the treatment of small articular cartilage defects. Several
studies show comparable results for autologous chondrocyte implantation (ACI) and
microfracture. Unfortunately, the fibrocartilage resulting from microfracture has neither
the structure nor the mechanical properties of hyaline cartilage, even though the adult