Mechanotransduction of Mesenchymal Stem Cells and Hemodynamic Implications

Abstract

Mesenchymal stem cells (MSCs) possess the capacity for self-renewal and multipotency. The traditional approach to manipulating MSC's fate choice predominantly relies on biochemical stimulation. Accumulating evidence also suggests the role of physical input in MSCs differentiation. Therefore, investigating mechanotransduction at the molecular level and related to tissue-specific cell functions sheds light on the responses secondary to mechanical forces. In this review, a new frontier aiming to optimize the cultural parameters was illustrated, i.e. spatial boundary condition, which recapitulates in vivo physiology and facilitates the investigations of cellular behavior. The concept of mechanical memory was additionally addressed to appreciate how MSCs store imprints from previous culture niches. Besides, different types of forces as physical stimuli were of interest based on the association with the respective signaling pathways and the differentiation outcome. The downstream mechanoreceptors and their corresponding effects were further pinpointed. The cardiovascular system or immune system may share similar mechanisms of mechanosensing and mechanotransduction; for example, resident stem cells in a vascular wall and recruited MSCs in the bloodstream experience mechanical forces such as stretch and fluid shear stress. In addition, baroreceptors or mechanosensors of endothelial cells detect changes in blood flow, pass over signals induced by mechanical stimuli and eventually maintain arterial pressure at the physiological level. These mechanosensitive receptors transduce pressure variation and regulate endothelial barrier functions. The exact signal transduction is considered context dependent but still elusive. In this review, we summarized the current evidence of how mechanical stimuli impact MSCs commitment and the underlying mechanisms. Future perspectives are anticipated to focus on the application of cardiovascular bioengineering and regenerative medicine.

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© 2023 Chinese Journal of Physiology | Published by Wolters Kluwer - Medknow 55
Review Article
Background of Mechanotransduction
Mesenchymal stem cells (MSCs) are known as broblast-like
cells that harbor the potential of proliferation and multipotency.
Manipulating expansion and lineage specication of MSCs
has attracted extensive research attention during the past
decades. However, except for the DNA methylation prole,
MSCs share similar characteristics in morphology and
specic mesenchymal markers with broblasts.[1] Moreover,
MSCs harvested from different anatomical origins are
heterogeneous in nature and express distinct Hox codes, which
have been implicated to preserve positional imprints and
specify topographic dierentiation.[2] From the perspective of
mechanistic interrogation, a detailed appreciation of molecular
pathways could propel advancements in tissue engineering.
Cell fate choice has long been known to be dependent on
biochemical induction. Dierent regimens for corresponding
lineage specication are ascertained and has been widely
Mechanotransduction of Mesenchymal Stem Cells and
Hemodynamic Implications
Ting-Wei Kao1, Yi-Shiuan Liu2, Chih-Yu Yang3,4,5, Oscar Kuang-Sheng Lee3,6,7,8,9*
1Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, 2School of Medicine, National Tsing Hua University, Hsinchu, Taiwan,
3
Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, 4Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung
University, Taipei, Taiwan, 5Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, 6Stem Cell Research Center, National
Yang Ming Chiao Tung University, Taipei, Taiwan, 7Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, 8Department of Orthopedics,
China Medical University Hospital, Taichung, Taiwan, 9Center for Translational Genomics and Regenerative Medicine Research, China Medical University Hospital,
Taichung, Taiwan
Mesenchymal stem cells (MSCs) possess the capacity for self-renewal and multipotency. The traditional approach to manipulating MSC’s
fate choice predominantly relies on biochemical stimulation. Accumulating evidence also suggests the role of physical input in MSCs
dierentiation. Therefore, investigating mechanotransduction at the molecular level and related to tissue-specic cell functions sheds light
on the responses secondary to mechanical forces. In this review, a new frontier aiming to optimize the cultural parameters was illustrated,
i.e. spatial boundary condition, which recapitulates in vivo physiology and facilitates the investigations of cellular behavior. The concept of
mechanical memory was additionally addressed to appreciate how MSCs store imprints from previous culture niches. Besides, dierent types
of forces as physical stimuli were of interest based on the association with the respective signaling pathways and the dierentiation outcome.
The downstream mechanoreceptors and their corresponding eects were further pinpointed. The cardiovascular system or immune system
may share similar mechanisms of mechanosensing and mechanotransduction; for example, resident stem cells in a vascular wall and recruited
MSCs in the bloodstream experience mechanical forces such as stretch and uid shear stress. In addition, baroreceptors or mechanosensors of
endothelial cells detect changes in blood ow, pass over signals induced by mechanical stimuli and eventually maintain arterial pressure at the
physiological level. These mechanosensitive receptors transduce pressure variation and regulate endothelial barrier functions. The exact signal
transduction is considered context dependent but still elusive. In this review, we summarized the current evidence of how mechanical stimuli
impact MSCs commitment and the underlying mechanisms. Future perspectives are anticipated to focus on the application of cardiovascular
bioengineering and regenerative medicine.
Keywords: Hemodynamics, mechanical memory, mechanotransduction, mesenchymal stem cell, spatial boundary condition
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*Address for correspondence: Dr. Oscar Kuang‑Sheng Lee,
School of Medicine, Institute of Clinical Medicine, National Yang Ming Chiao
Tung University, No. 155, Section 2, Li‑Nong Street, Beitou, Taipei 112,
Taiwan.
E‑mail: oscarlee9203@gmail.com
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How to cite this article: Kao TW, Liu YS, Yang CY, Lee OK.
Mechanotransduction of mesenchymal stem cells and hemodynamic
implications. Chin J Physiol 2023;66:55-64.
Abstract
Received: 24-Nov-2022 Revised: 14-Mar-2023 Accepted: 16-Mar-2023
Published: 20-Apr-2023
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Kao, et al.: Interplay of forces and mesenchymal stem cells
56 Chinese Journal of Physiology ¦ Volume 66 ¦ Issue 2 ¦ March-April 2023
applied in cell culture.[3] Interestingly, studies observed
that the induction modalities were not only limited to the
pharmaceutical approach but also extended to mechanical
stimuli.[4] The concept of mechanotransduction emerged to
address the role of physical input in stem cell dierentiation.
At first, the literature investigated the effect exerted by
substrate rigidity. A stier scaold was demonstrated to bias
MSC toward osteoblast maturation, whereas a soft one was
toward adipocyte.[5] Follow-up research inquired about the
role of other cultural parameters, for example, porous size
and dimensionality, and the types of exerted force in the
dierentiation process.[6] Besides, whether and how cells
preserve previous mechanical imprints remained enigmatic.
The concept of “mechanical memory” emerged to depict such
phenomena.[7] These preliminary studies triggered the search
for mechanical responders and relevant signaling pathways
in MSCs.
The mechanisms regarding how MSCs perceive mechanical
stimuli remain unclear. For example, the altered behavior of
local MSCs residing within the vascular lumen exemplies
the eect of hemodynamic stimulation. Yet, how cells respond
to the mechanotransduction signaling from the perspective
of cardiac and vascular pathophysiology has not been
fully comprehended. Recently, cardiovascular applications
have emerged as a novel eld for developing translational
medicine. Resident stem cells were proposed to be pivotal
in the formation of blood vessels and the pathogenesis
of atherosclerosis.[8,9] In contrast, angiogenesis and the
orchestration of anti-inammatory properties were exhibited
to be mediated by MSCs.[10] Literature that demonstrated the
molecular mechanism of MSCs mechanotransduction, the
eects exerted by mechanical characteristics of cultural niches,
or the clinical implications, especially regarding hemodynamic
parameters, was revisited [Table 1]. These studies demonstrate
that the mechanical properties of the microenvironment
modulate the fate commitment of MSCs.
How stem cells respond to mechanical stimuli is an ongoing
endeavor. Petzold and Gentleman described the impact of
mechanotransduction on cell fate choice from the perspective
of embryogenesis instead of physiopathogenesis.[11] Raman
et al. elegantly summarized those factors that participated in
mechanotransductive pathways in a mechanistic fashion.[12]
In this article, we aimed to delineate the mechanotransductive
pathway of MSCs. Critical factors in cell culture and
application were further pragmatically recognized.
the MechanisM governing Mechanotransductive
signaling
In which manner the mechanical force is transmitted
to impact stem cell lacks full consensus [Figure 1].
The “force-from-lipid” addressed the role of lipids in
mechanotransduction. Such principle was proposed based on
the understanding of prokaryotic physiology. This framework
argues that exogenous force is directly transferred through
phospholipid bilayers, thereby orchestrating channel gating.
Escherichia coli small-conductance and large-conductance
mechanosensitive channels (MscS and MscL) were identied
as the mechanosensitive responders.[13] Nevertheless, dierent
signaling transductions were observed in eukaryotic organisms.
Another concept termed “force-from-lament” pinpointed the
alteration of intracellular architecture in mechanotransductive
pathways. This principle underscored the relevance of
the cytoskeleton and focal adhesion components in force
transduction. For example, diaphanous-related formin was
pinpointed to govern the arrangement of intranuclear lamin and
the cell fate commitment of marrow-derived MSCs.[14] These
two major principles constitute the backbone of intracellular
pathways for mechanotransduction.[15]
The mechanotransduction pathway is dissected into three
essential elements for better understanding. Firstly, the types
of exerted force, for example, uid shear stress, hydrostatic
pressure, and normal force loading determine which kind of
physical stimuli is imparted. The second element refers to
corresponding mechanosensors. Piezo-type mechanosensitive
ion channel component 1/2 (Piezo1/2) and transient
receptor potential cation channel subfamily M member
7 (TRPM7) are the examples proposed to be involved in signal
transduction.[16] Piezo family, as one type of calcium channel,
answers to dynamic uid shear force and aects cell migration
by releasing adenosine triphosphate for transducing signal to
downstream bone morphogenetic protein 2 (BMP2). A recent
Figure 1: Key signaling pathways in mechanotransduction. BMP: Bone
morphogenetic protein, cAMP: Cyclic adenosine monophosphate, GPCR:
G‑protein‑coupled receptor, mTOR: Mammalian target of rapamycin,
NICD: Notch intracellular domain, PI3K: Phosphoinositide 3‑kinases,
Piezo1/2: Piezo type mechanosensitive ion channel component, ROCK:
Rho‑associated protein kinase, YAP/TAZ: Yes‑associated protein
1/transcriptional co‑activator with PDZ‑binding motif.
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Chinese Journal of Physiology ¦ Volume 66 ¦ Issue 2 ¦ March-April 2023
in vivo study based on a murine model also demonstrated that
Piezo1 acts as a mechanosensory of cardiomyocytes to result
in maladaptive hypertrophy in response to pressure overload
by inducing calcium inux to activate TRPM4.[17] These are
categorized as mechanosensitive channels and lament-linked
mechanosensors. Third, the mechanotransduction pathway
is initiated through the corresponding alterations of cellular
physiology. For instance, the compression and stretching of
the extracellular matrix were intertwined with neural stem
cell dierentiation.[18] Integrin and focal adhesion were also
recognized to transduce mechanical impact.[19] In addition, the
axis of downstream molecules in the cytoplasm and within
the nucleus, for example, BMP2, intracellular Runt-related
transcription factor 2 (Runx2), and transcription factor SP7,
were pinpointed to be impacted by mechanical forces and bring
about osteoblastogenesis.[20] The eect of mechanical stimuli
was further demonstrated at the epigenetic level. MicroRNA-9
and microRNA-10 were proposed to regulate force-manipulated
Runx2 expression during dierentiation.[21] Lee et al. also
demonstrated that microRNA-10a not only responds to
dierent hemodynamic forces but also interacts with retinoic
acid receptors and histone deacetylases, therein altering the
inammatory status of the endothelium at the vascular wall.[22]
In addition, the role of nuclear mechanosensing was addressed.
Through the linker of the nucleoskeleton and cytoskeleton,
the mechanical inputs are transduced into the nucleus and
alter chromatin structure as well as transcription factors.[23]
Elucidations toward the mechanism of mechanotransduction
facilitated the understanding of how MSCs respond to physical
stimuli.
spatial Boundary condition as a Mechanical
Modulator
The characteristics of cultural material determine the niche
for MSCs dierentiation. Exertion of the mechanical stimulus
also hinges on the manipulation of the local microenvironment.
Spatial boundary condition refers to the physical peculiarities
of the surroundings, and tensegrity describes the adaptation
of focal adhesion and cytoskeleton realignment. Early
studies exhibited the correlation between matrix rigidity and
MSC lineage specication,[24] possibly through remodeled
cell shape and tension of the cytoskeleton.[25] Recent
transcriptome analysis further identied the role of long
Table 1: Components of mechanotransduction signaling and their respective effects
Type Definition Role
Force
Shear force Force parallel to the luminal wall Shear force orients F-actin and β-catenin to polarize MSCs[2]
Hydrostatic pressure Force perpendicular to luminal
wall
Hydrostatic pressure translocates Smad2 into nucleus to promote ossication
of endochondrocytes[51]
Stretching force Force in line of circumferential
direction to luminal wall
Stretching force nurtured the mechanical resistance of local stem cells[54]
Spatial boundary condition
Rigidity The stiness of cell-residing
matrix
Rigidity of culture substrate governs viscoelasticity and subsequently the
dierentiation of MSCs[23]
Dimensionality Stereoscopic/attened surface for
cell culture
Three-dimensional microenvironment recapitulates in vivo condition[32]
Mechanical memory Imprinting of mechanical input
from the previous niche
YAP/TAZ and RUNX2 were proposed to store longitudinal memory and
impact lineage specication[41]
Conduction
Via lipid Through phospholipid bilayers MscS and MscL were recognized as the mechanoresponders in
force-from-lipid principle[13]
Via lament Through cytoskeleton and focal
adhesion
Diaphanous-related formin impacts fate choice of MSCs in mediation of
intracellular actin-lamin[14]
Antxr1 responses to focal adhesion and facilitates endochondral osteogenesis[52]
Mechanoreceptors and responders
Piezo1/Piezo2 Calcium channel/propioreceptor Piezo1 releases ATP to guide cell migration and interact with downstream
BMP2[17,54,56,57]
Piezo2 locating at aortic depressor nerve responds to uctuating blood pressure
and heart rate[64,65]
TRPM7 Calcium channel TRPM7 is essential for MSC survival and correlated with Osterix to guide
dierentiation[16,58-60]
Tentonin 3 Baroreceptor Tentonin 3 is prerequisite for the maintenance of action potential[66]
GPR68 Cation channel GPR68 modulates local vascular resistance in response to uidic shear
stress[67,68]
Antxr1: Anthrax toxin receptor 1, ATP: Adenosine triphosphate, BMP2: Bone morphogenetic protein 2, GPR68: G-protein-coupled receptor 68, MSC:
Mesenchymal stem cell, MscS/L: Mechanosensitive channels of small/large conductance, Piezo1/2: Piezo-type mechanosensitive ion channel component
1/2, RUNX2: Runt-related transcription factor 2, Smad2: Mothers against decapentaplegic homolog 2, TRPM7: Transient receptor potential cation channel
subfamily M member 7, YAP/TAZ: Yes-associated protein 1/transcriptional co-activator with PDZ-binding motif
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Kao, et al.: Interplay of forces and mesenchymal stem cells
58 Chinese Journal of Physiology ¦ Volume 66 ¦ Issue 2 ¦ March-April 2023
non-coding RNAs (lncRNAs) in reflecting the effect of
spatial boundary conditions. The lncRNAs possess specic
subcellular distribution and modulate genetic expression.
Epitomized by MSC osteogenesis, Zhang et al. proled six
lncRNAs with regulatory potential.[26] Specically, lnc00458
presents in only undierentiated human MSCs and serves as
the promoter for NANOG.[27] Lnc00458 responds to substrate
stiness and facilitates the maturation of multipotent stem cells
toward endoderm.[28] In addition, the cytoskeleton rearranges
concurrently with the course of lineage specication. Chen
et al. illustrated that the actin laments rearranged and became
thicker during osteoblast dierentiation. The intracellular
viscoelasticity converts from viscous-like to elastic-like during
osteogenic dierentiation but remains viscous-like during
adipogenesis.[29] The alterations of physical properties further
modulate downstream intracellular gene activities[30] and
exemplify the mechanical impact on cell fate choice.
Another aspect of mechanotransduction relates to
dimensionality. The conventional approach predominantly
utilizes Petri dishes for cell culture; yet, the topographical
dierence between such articial niches and physiological
conditions confounds the observation of stem cell
dierentiation. In our previous study, three-dimensional
polyacrylamide scaffolds were manufactured with
two distinct rigidities to recapitulate in vivo substrate
stiffness and interrogate the effects of intracellular
viscoelasticity.[31] Through passive microrheology, the sti
substrate was illustrated to escalate Young’s modulus and vice
versa. The three-dimensional scaolds were demonstrated
to better promote osteogenesis under concomitant chemical
induction compared to two-dimensional scaolds.[32] Gelatin
can be used to fabricate three-dimensional scaolds with
tunable pore sizes. The optimized spherical diameters were
100 and 150 μm for osteogenesis, by which α2 and α5
integrins were illustrated to transduce the mechanical signal
generated by the curvature of the scaolds.[33] Gelatin or
polyacrylamide are the most popular ingredients for scaold
fabrication, while culture materials, e.g., thixotropic gels,
were also feasible.[34] Besides, the expressions of cadherin-2
and cadherin-11 diered in aggregate and monolayer culture,
thereby linking dimensionality’s impact on cell fate choice.[35]
These results addressed the characteristics of the cultural
microenvironment modulates the mechanotransduction.
effect of Mechanical MeMory
The longitudinal eect is another parameter that could aect
MSC differentiation. Literature suggests that MSCs can
conserve the information regarding the previous cultural
niche, by which mechanically induced differentiation is
inuenced. To investigate this “mechanical memory,” Wu et al.
manufactured an elastomeric nanohybrid matrix with a stiness
thermo-responsive. The initial rigidity and subsequent
softening of substrate tuned by temperature were intertwined
with the in vitro chondrogenic dierentiation of MSCs.[36]
Literature also demonstrated that the mechanical memory of
initial culture expansion on a sti matrix compromised the
adipogenic potential of stem cells.[37] These ndings inspired
further studies on the interplay between mechanical switching
and lineage specication.
Although the exact mechanism responsible for mechanical
memory remains obscure, a mathematical model was
established for better elucidation.[38] In this network, the genetic
region orchestrating the physical imprint was delineated in
conjunction with the demonstration of the predictive capability
of MSC fate choice. Yang et al., on the other hand, considered
the “dosage” of such mechanical memory.[39] Upon cell
culturing on the sti scaold, either reversible or irreversible
activation of the osteogenic markers was observed with
dierent intensities of mechanical imprinting. Subsequent
literature endorsed the impact of the priming phase upon
terminal differentiation. Furthermore, three-dimensional
chromatin reorganization correlated with the transcriptome’s
dynamic landscape.[40] Specically, Yes-associated protein 1/
transcriptional co-activator with PDZ-binding motif (YAP/
TAZ) and Runx2 were reported to be responsible for storing
previous mechanical memory and thereby alternating
subsequent lineage specications.[41] The actin-actin bonding
and polarity of depolymerization under cyclic force were
also critical in transducing the temporal mechanical eect
on stem cell dierentiation.[42] Conjunctionally, substrate
stiness-dependent activation of Wnt/β-catenin signaling
participates in mechanotransduction. The expression of Wnt
and β-catenin is altered by extracellular matrix elasticity via
integrin and focal adhesion responses and stores mechanical
stimuli to further regulate cell fate.[43,44] As for epigenetic
modications, the mechanical stimuli were illustrated to
remodel and memorize chromatin’s architecture. Interestingly,
recent in vitro studies demonstrated that human MSCs
cultured on rigid substrates for 10 days exhibited irreversible
histone acetylation even after substrate softening.[45]
Megakaryoblastic Leukemia 1,2 gene and Serum Response
Factor were hypothesized to orchestrate the reprogramming
of dierentiation lineage by controlling the accessibility of
the genome.[46]
In addition, the duration of cell culture was considered to
inuence the dynamic changes of mechanically regulated
dierentiation. Specically, microRNA miR-21 was pinpointed
as a sensor with memory. Previous literature has recognized
miR-21 to correspond with mechanical input and guide stem
cells toward osteogenesis through the activated mothers
against decapentaplegic homolog 2 (Smad2)/Runx2 signaling
pathway.[47] Manipulating this microRNA erased previous
memory and, for further induction, achieved resensitization.[48]
These results together challenged the current culture protocol,
as stem cells are predominantly maintained and expanded
in a rigid microenvironment at a very early stage. Whether
the dierentiation potency would be preserved regarding
mechanical memory is amidst ongoing arguments.[49] Together,
the mechanical imprints alter subsequent lineage specications
of MSCs.
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Kao, et al.: Interplay of forces and mesenchymal stem cells
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Chinese Journal of Physiology ¦ Volume 66 ¦ Issue 2 ¦ March-April 2023
type of force and Mechanoreceptors
To appreciate the mechanical eect on MSC proliferation and
cell fate choice, two aspects are considered: the type of forces
and their corresponding mechanosensors. The most widely
investigated mechanical input was the shear force, dened as
the mechanical input in a tangential direction with respect to
the lumen. Chen et al. proposed that the laminar shear force
guided F-actin orientation and MSC polarization, which
eventually led to cardiovascular maturation and angiogenesis.[2]
Laminar shear force against the inner endothelium, i.e. tunica
intima, was also demonstrated to promote local endothelial
cell dierentiation.[50] In addition, oscillatory shear stress was
exhibited to alter the organization of F-actin and orchestrate
β-catenin to determine lineage specication.[51] For example,
bronectin as the ligand of focal adhesions was proposed to
participate in ossication. Anthrax toxin receptor 1 (Antxr1)
was recently identied as mandatory in endochondral bone
formation.[52] Regulated by osteogenic marker Runx 2, Antxr1
participated in the mechanotransduction of bone marrow
stromal cells. Another type of force is the hydrostatic pressure
that acts perpendicular to the luminal wall. In conjunction
with shear force, these interactively bring about the nuclear
translocation of Smad2 to propel endochondral ossication.[53]
Other signicant classications included stretching force. In
line with the circumferential direction of the tubal surface, the
resulting strain was proposed to facilitate the dierentiation
and further enhance the mechanical resistance of residing skin
stem cells locally.[54]
As for other downstream mechano-responders, several genes were
pinpointed to be involved in regulating stem cell dierentiation.
First, Piezo1 has been extensively studied for its role in
mechanotransduction due to its kinetics of rapid inactivation.[55]
As a calcium channel, Piezo1 responds to external stimuli by
releasing adenosine triphosphate and inuencing the migration of
dental pulp-derived MSCs.[56] Moreover, Piezo1 was suggested
to inuence MSC dierentiation through BMP2. Sugimoto et al.
discovered that osteogenesis induced by hydrostatic pressure
was dependent on Piezo1-regulated BMP2.[57] Nonetheless,
although Piezo1 has been well demonstrated to be correlated
with mechanotransduction, whether this stretch-sensitive
baroreceptor participates in signaling transduction or acts as
a bystander warranted further validation. Second, TRPM7
is pivotal for MSC mechanotransduction in bone formation.
An early study suggested that TRPM7 is a prerequisite to
maintaining MSC viability.[58] It also addressed that TRPM7
might be involved in the dierentiation thereof. Intertwined with
the downstream BMP2/Smad/Runx2/Osterix axis, TRPM7 was
displayed to perceive intermittent uid shear stress and indicated
to promote endochondral/intramembranous ossification.[59]
An in vitro study further demonstrated that the knockdown of
TRPM7 prevented mechanically induced calcium inux and
osteogenesis in MSCs.[60]
Recently, various studies revealing molecular mechanisms of
pressure sensing in the cardiovascular system could facilitate a
better understanding of mechanosensing in cellular physiology.
An interesting topic reflecting mechanotransduction is
baroreex, i.e., the mechanism that maintains homeostasis
of blood pressure by sensing intraluminal pressure. Those
mechanoreceptors aggregating at the common carotid artery,
carotid sinus, and aortic arch sustain arterial pressure. The
autonomic activity and vascular tone are subsequently adjusted
accordingly to maintain hemodynamic homeostasis.[61]
Members of the Piezo family are prerequisites for this reex.[62]
Zeng et al. proposed that Piezo1 located on the sensory ganglion
was significant in blood pressure control through its
mechanosensing ability.[63] Min et al. employed a genetic
approach and pinpointed Piezo2 in the aortic depressor nerve
to participate in mechanotransduction.[64] The alteration of
blood pressure and heart rate was erased once the Piezo2
neurons were ablated. This was clinically signicant since
compromised baroreex has been related to an increased
risk of coronary artery disease and heart failure.[65] Another
mechanically evoked cation channel was Tentonin 3. Animal
studies demonstrated that tentonin 3 knockout interfered with
the stability of action potentials by pressure stimuli.[66] Other
clinical consequences included tachycardia and elevated mean
arterial blood pressure. Another pivotal player in vascular
physiology was G-protein coupled receptor 68 (GPR68).
As a mechanoreceptor in the endothelium, GPR68 reacted
to uid shear stress and altered local vascular resistance.
Specically, GPR68 responds to extracellular acidosis and
activates either the phospholipase C formation and the
calcium ux from the endoplasmic reticulum or the release
of adenylyl cyclase/cyclic adenosine 3’,5’-monophosphate
pathway into the cell for maintaining contractile phenotype.[67]
Rodent experiments further suggested a deciency in GPR68
prevented ow-induced vasodilation.[68] Together, these studies
highlighted how the mechanical eect aects uid dynamics.
Furthermore, whether these mechanoreceptors play similar
roles in stem cells or other types of cells is worth further
investigation.
Mechanotransduction and cardiovascular
iMplications
Based on a translational viewpoint, a detailed appreciation
of the mechanotransductive property is a prerequisite for
understanding the pathogenesis and pinpointing the therapeutic
target [Table 2]. A longitudinal analysis of publication count
highlighted the constant attention on the cardiovascular
translation of MSC manipulation.[69] First, heart failure
has been the major clinical burden among cardiovascular
etiologies. The hallmark of the pathogenesis was accounted as
remodeling maladaptation and ultimate decompensation. In the
presence of stress, for example, ischemia and inammation,
the quiescent resident broblasts would be induced for lineage
specication toward myobroblasts and thereby accumulate
collagen and excessively produce focal adhesion.[70] Enhanced
mechanical burden stiens the myocardium, which eventually
brings about scarring. Conversely, the rigidied substrate also
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Kao, et al.: Interplay of forces and mesenchymal stem cells
60 Chinese Journal of Physiology ¦ Volume 66 ¦ Issue 2 ¦ March-April 2023
promoted the migration and dierentiation of broblasts. The
Hippo pathway involving YAP/TAZ was considered relevant
to the mechanotransduction, as demonstrated by a murine
cell line.[71] Stiened extracellular matrix further deteriorated
cardiac pumping functions and eventually led to heart failure.
Another aspect regarding the mechanical eect on cardiac
function is valvular physiology. Embryological studies
suggested that the regurgitant ow promoted the recruitment
of endocardial cells, the morphogenesis of valve leaets, and
cardiac chamber formation by cytoskeleton rearrangement.
Endocardial-mesenchymal transition and shear force also
participated in this process.[72] Similar to the pathogenesis
of heart failure, dormant valve interstitial cells responding
to maximal shear stress were predisposed to aortic valve
calcication through the alteration of cytoskeleton mechanical
properties secondary to physical stimuli. Bouchareb et al.
pinpointed RhoA/rho-associated protein kinase as the key
factor in manipulating the migration of YAP into the nucleus
in response to mechanical stimuli on the cytoskeleton.[73] A
disease-in-a-dish model was established to recapitulate the
pathophysiological cardiac valvulogenesis.[74] Illuminated by
mitral valve prolapse, the platform identied specic genetic
defects that predisposed extracellular matrix derangement and
subsequently impacted the mechanotransduction of resident
stem cells.[75]
In addition, mechanical impact contributes to atherosclerosis.
Optimization of vascular elasticity is a prerequisite to
maintaining the normal physiology of blood vessels. The
governing factor was attributed to the fluid shear force.
Krüppel-like factor-2 was proposed as the key player
in transducing mechanical stimuli toward the vascular
endothelium.[76] Arterialization was proposed to reflect
shear-manipulated ephrinB2 gene expression. As for the
extracellular architecture, the rigidity of the local niche
was demonstrated to determine cell fate choice. Wong et al.
reported that the sti substrate bias the vascular progenitor cells
toward smooth muscle through the Notch signaling pathway,
while the soft matrix promotes endothelium formation.[77]
Remodeling of the vascular wall was also involved with
physical input, as the rearrangement of vimentin intermediate
laments responded to the exerted pulsatile force.[78] Moreover,
an inadequate adaptation of the local mechanical input brings
about pathological consequences. Metalloproteases secreted
from smooth muscle cells were pinpointed to be corresponding
with altered hemodynamics. Stem cells were also proposed
to participate in immunomodulatory eects regarding the
pathogenesis of atherosclerosis.[79]
Besides, MSCs were proposed to be mobilized from bone
marrow and participate in neoangiogenesis for vascular repair.
Vascular endothelial cells sense disturbed shear ow and
responded to the mechanical stress by initiating the transduction
signal of PKA-MAPK-Akt, Ras/PI3K/Akt pathways, as well
as the activation of the inux calcium channel. In conjunction,
integrins, vascular endothelial growth factor receptors, receptor
tyrosine kinases, and G protein-coupled receptors are the
pivotal mechanosensors that perceive the pathological input
of disturbed blood ow.[80] The endothelial progenitor cells
are eventually stimulated for induction toward the formation
of endothelium lining and smooth muscle cells. The small
Rho GTPases, RhoA, Cdc42, and Rac1 are pinpointed to alter
the transcription process.[81] Another mechanosensor was the
mammalian target of rapamycin couple 2, which is activated
by focal adhesion and rearranges the F-actin of MSCs.[82]
Furthermore, Chen et al. illustrated that laminar shear stress
facilitated β-catenin nuclear localization and changed the
polarity of MSCs to promote angiogenesis.[2] As exemplied
by the injury of the abdominal aorta, MSCs were demonstrated
to migrate from adjacent intact intima and subsequently
dierentiated into smooth muscle cells for vessel repair and
formation.[83] Future perspectives will focus on the clinical
application of stem cells in cardiovascular disease management.
Exemplied by recapitulating ischemic heart disease, priming
MSCs with oxidative stress was demonstrated to facilitate
engraftment and cardiogenic dierentiation. In conjunction,
stimulation with transforming growth factor-β, BMP-4, and
interleukin-6 further promoted the generation of “cardiopoietic”
stem cells for modeling ischemic cardiomyopathy.[84] Yet, the
clinical translation of manipulating MSCs still awaits further
validation.
future perspective and clinical translation
Further integrative investigations toward the factors
participating in mechanotransduction pathways were grounded
on emerging technologies. Computational mathematical
modeling serves as a state-of-the-art modality for analyzing
cellular behaviors at the molecular level. The molecular theory
Table 2: Mechanotransduction of stem cells correlates with the pathogenesis of cardiovascular diseases
Disease Pathogenesis in mechanical perspective Cellular responses and signaling transduction
Heart failure Maladaptative to excessive hemodynamic loading and
eventually aggravating to decompensatory remodeling
Local quiescent cells were induced dierentiation toward
myobroblast and resulted in scaring through YAP/TAZ
in the Hippo pathway[71]
Valvular heart
disease
Dysfunctional leaet, chordae, or papillary muscle leads
to nonphysiological blood ow within cardiac chambers
Regurgitant shear force activates indwelling dormant
cells to bring about valve calcication via Rho/ROCK[73]
Atherosclerosis Degeneration and stiening of vascular wall
characterized by intraluminal thickening and secondary
to overloaded luminal shear force
Fluid shear force stimulates the vascular endothelium
and interacts with extracellular matrix depending on the
mediation of Klf2, ephrinB2 and Notch signaling[76]
Klf2: Krüppel-like factor 2, ROCK: Rho-associated protein kinase, YAP/TAZ: Yes-associated protein 1/transcriptional co-activator with PDZ-binding motif
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Kao, et al.: Interplay of forces and mesenchymal stem cells
61
Chinese Journal of Physiology ¦ Volume 66 ¦ Issue 2 ¦ March-April 2023
of motor clutch demonstrates the eect exerted through matrix
rigidity upon force transmission.[85] Besides, to confer the
confounding mechanical input and for precise quantication
of the force applied, together with atomic force microscopy,[86]
video particle tracking microrheology was developed as well.
Intracellular viscoelasticity[87] and the mechanical responses to
external cytokines were depicted using such platform[88] during
cell dierentiation. Employing the tension sensor of Förster
resonance energy transfer to dene the force gradient[89] and
further to the assessment at the single-molecule level[90] are
advanced illustrations reecting the industrial evolvement of
experimental apparatus to analyze mechanotransduction. These
advancements propelled a more accurate appraisal of MSCs’
physiology and dierentiative behaviors.
On the clinical end, the frontier for MSC mechanotransduction
addressed the translation in cardiovascular applications.
Aside from previous experience in other elds, the advanced
understanding of the physical stimuli inspired interest in how
hemodynamics aects the physiology of local stem cells.
For instance, atherosclerosis and elevated blood pressure
intensify the mechanical loading on the vascular wall. How
the indwelling stem cells respond was elusive. Likewise, the
turbulent ow secondary to valvular regurgitation causes a
mechanical impact on the intra-cardiac stem cell.[91] An in vivo
study demonstrated that the steady, pulsatile shear stress or no
ow condition dierently altered the actin lament organization
of MSCs.[92] Recognition of such mechanotransduction propels
the manufacturing of articial heart valves for transplantation
purposes. In conjunction with the cellular construction of other
cardiac components, i.e. ventricle musculature for pumping,
future elucidations toward the respective mechanical signals
and MSCs adaptation will realize the cellular therapeutics.
potential therapeutics utilizing MesenchyMal
steM cells
Utilizing stem cells for therapeutic purposes in the
cardiovascular field is promising.[93] The rationale for
employing MSCs relies on self-renewing potential and
the potency to dierentiate into cardiomyocytes and other
lineages. Preclinical studies have interrogated the ecacy
of manipulating stem cells for attenuating ischemic injury
in the myocardium. In the PROMETHEUS (Prospective
Randomized Study of MSC Therapy in Patients Undergoing
Cardiac Surgery) trial, intramyocardial injection of autologous
stem cells was demonstrated to improve both regional and
global left ventricular function after cardiac operation. The
major mechanism underlying the benet was ameliorating
tissue fibrosis, promoting angiogenesis, and facilitating
myogenesis.[94] As for intracoronary injection of stem cells,
albeit theoretically feasible, to date there is no concrete
evidence to endorse such a therapeutic measure. Future
case-controlled studies are expected to validate its ecacy.
Another modality of MSC therapeutics is to manipulate the
local residing stem cells. Although with limited dierentiation
potential, those stem cells located at the vascular wall were
demonstrated to contribute to cardiomyocyte formation.
Hypothetically, the intima senses the vascular shear ow and
is mechanically impacted through vascular endothelial growth
factor receptor-2 receptor, phosphoinositide 3-kinase-Akt
pathway, and protein kinase C-mitogen-activated protein
kinase-extracellular signal-regulated kinase.[95] Interestingly,
Mekala et al. proposed these stem cells dwelling in
the outer layer of endothelium, i.e. adventitia, can also
specify to functional myocytes under appropriate culture
niches, possibly through mechanotransduction.[96] Eective
employment of stem cell therapy will be an innovative
approach to manage heart failure with reduced ejection
fraction as well as for vascular repair. Future in vivo studies
are mandatory to determine optimized parameters of the
cultural microenvironment for applying to cardiovascular
disease models as well as to demonstrate the ecacy and
safety of such treatments.
conclusions
Mechanotransduction plays an important role in MSC
phenotype and dierentiation. Recent studies propelled
the optimization of physical parameters regarding the
microenvironment for cell culture. Rigidity, spherical
size, and dimensionality of the microenvironment were all
proposed to impact the lineage specication. Furthermore,
“time” is also a crucial component as the previous cultural
condition is imprinted as mechanical memory and thereby
inuences subsequent fate commitments. Understanding
how to tune the dierentiation and stemness properties of
MSCs mechanically will help us to better dene the cellular
quality for clinical application. Dierent types of forces and
the corresponding mechanoreceptors have been pinpointed to
elucidate the underlying molecular mechanism. Additionally,
intertwined with two governing principles, force-from-lipid
as well as force-from-lament, and in conjunction with
biochemical stimuli, the mechanical stimuli alter cellular
physiology. In the cardiovascular system, the versatile
mechanosensing is reected in stretch-sensitive ion channels
Piezo1/Piezo2 and Tentonin 3 in baroreex, as well as shear
ow-sensitive GPR68 in small-diameter vessels. As for
clinical implications, the observation of mechanical eects
in the cardiovascular system will facilitate their manipulation
of local stem cells for bioengineering, cellular therapy, and
regenerative medicine.
Authors’ contributions
TWK, LYS, CYY, and OKL conceived and designed the study.
TWK and LYS conducted the literature review. TWK prepared
the manuscript. LYS, CYY, and OKL edited the article. The
study was under the supervision of CYY and OKL. All authors
have read and approved the nal manuscript.
Financial support and sponsorship
The authors received financial support for research
purposes from the National Science and Technology
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Kao, et al.: Interplay of forces and mesenchymal stem cells
62 Chinese Journal of Physiology ¦ Volume 66 ¦ Issue 2 ¦ March-April 2023
Council, Taiwan (MOST 109-2314-B-010-053-MY3;
MOST 110-2811-B-010-510; MOST 110-2321-B-A49-003;
NSTC 111-2923-B-007-001-MY3), Taipei Veterans
General Hospital (V111C-155; V111D63-003-MY2-1;
VGHUST111-G6-7-2), and the Center for Intelligent Drug
Systems and Smart Bio-devices (IDS2B) from The Featured
Areas Research Center Program within the framework of
the Higher Education Sprout Project by the Ministry of
Education, Taiwan. The funders have no role in study design,
data collection, analysis, interpretation, or manuscript writing.
Conflicts of interest
The authors declare that the research was conducted in the
absence of any commercial or nancial relationships that could
be construed as a potential conict of interest.
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