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Table of Contents
Year : 2023  |  Volume : 66  |  Issue : 2  |  Page : 55-64

Mechanotransduction of mesenchymal stem cells and hemodynamic implications

1 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
2 School of Medicine, National Tsing Hua University, Hsinchu, Taiwan
3 Institute of Clinical Medicine, National Yang Ming Chiao Tung University; Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University; Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
4 Institute of Clinical Medicine, National Yang Ming Chiao Tung University; Stem Cell Research Center, National Yang Ming Chiao Tung University; Department of Medical Research, Taipei Veterans General Hospital, Taipei; Department of Orthopedics, China Medical University Hospital; Center for Translational Genomics and Regenerative Medicine Research, China Medical University Hospital, Taichung, Taiwan

Date of Submission24-Nov-2022
Date of Decision14-Mar-2023
Date of Acceptance16-Mar-2023
Date of Web Publication20-Apr-2023

Correspondence Address:
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
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cjop.CJOP-D-22-00144

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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.

Keywords: Hemodynamics, mechanical memory, mechanotransduction, mesenchymal stem cell, spatial boundary condition

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

How to cite this URL:
Kao TW, Liu YS, Yang CY, Lee OK. Mechanotransduction of mesenchymal stem cells and hemodynamic implications. Chin J Physiol [serial online] 2023 [cited 2023 Nov 30];66:55-64. Available from: https://www.cjphysiology.org/text.asp?2023/66/2/55/374410

  Background of Mechanotransduction Top

Mesenchymal stem cells (MSCs) are known as fibroblast-like cells that harbor the potential of proliferation and multipotency. Manipulating expansion and lineage specification of MSCs has attracted extensive research attention during the past decades. However, except for the DNA methylation profile, MSCs share similar characteristics in morphology and specific mesenchymal markers with fibroblasts.[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 differentiation.[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. Different regimens for corresponding lineage specification are ascertained and has been widely 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 differentiation. At first, the literature investigated the effect exerted by substrate rigidity. A stiffer scaffold 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 differentiation 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 exemplifies the effect 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 field 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-inflammatory properties were exhibited to be mediated by MSCs.[10] Literature that demonstrated the molecular mechanism of MSCs mechanotransduction, the effects 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.
Table 1: Components of mechanotransduction signaling and their respective effects

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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 Top

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 identified as the mechanosensitive responders.[13] Nevertheless, different signaling transductions were observed in eukaryotic organisms. Another concept termed “force-from-filament” 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]
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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The mechanotransduction pathway is dissected into three essential elements for better understanding. Firstly, the types of exerted force, for example, fluid 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 fluid shear force and affects cell migration by releasing adenosine triphosphate for transducing signal to downstream bone morphogenetic protein 2 (BMP2). A recent 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 influx to activate TRPM4.[17] These are categorized as mechanosensitive channels and filament-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 differentiation.[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 effect of mechanical stimuli was further demonstrated at the epigenetic level. MicroRNA-9 and microRNA-10 were proposed to regulate force-manipulated Runx2 expression during differentiation.[21] Lee et al. also demonstrated that microRNA-10a not only responds to different hemodynamic forces but also interacts with retinoic acid receptors and histone deacetylases, therein altering the inflammatory 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 Top

The characteristics of cultural material determine the niche for MSCs differentiation. 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 specification,[24] possibly through remodeled cell shape and tension of the cytoskeleton.[25] Recent transcriptome analysis further identified the role of long non-coding RNAs (lncRNAs) in reflecting the effect of spatial boundary conditions. The lncRNAs possess specific subcellular distribution and modulate genetic expression. Epitomized by MSC osteogenesis, Zhang et al. profiled six lncRNAs with regulatory potential.[26] Specifically, lnc00458 presents in only undifferentiated human MSCs and serves as the promoter for NANOG.[27] Lnc00458 responds to substrate stiffness and facilitates the maturation of multipotent stem cells toward endoderm.[28] In addition, the cytoskeleton rearranges concurrently with the course of lineage specification. Chen et al. illustrated that the actin filaments rearranged and became thicker during osteoblast differentiation. The intracellular viscoelasticity converts from viscous-like to elastic-like during osteogenic differentiation 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 difference between such artificial niches and physiological conditions confounds the observation of stem cell differentiation. 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 stiff substrate was illustrated to escalate Young's modulus and vice versa. The three-dimensional scaffolds were demonstrated to better promote osteogenesis under concomitant chemical induction compared to two-dimensional scaffolds.[32] Gelatin can be used to fabricate three-dimensional scaffolds 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 scaffolds.[33] Gelatin or polyacrylamide are the most popular ingredients for scaffold fabrication, while culture materials, e.g., thixotropic gels, were also feasible.[34] Besides, the expressions of cadherin-2 and cadherin-11 differed 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 Top

The longitudinal effect is another parameter that could affect MSC differentiation. Literature suggests that MSCs can conserve the information regarding the previous cultural niche, by which mechanically induced differentiation is influenced. To investigate this “mechanical memory,” Wu et al. manufactured an elastomeric nanohybrid matrix with a stiffness thermo-responsive. The initial rigidity and subsequent softening of substrate tuned by temperature were intertwined with the in vitro chondrogenic differentiation of MSCs.[36] Literature also demonstrated that the mechanical memory of initial culture expansion on a stiff matrix compromised the adipogenic potential of stem cells.[37] These findings inspired further studies on the interplay between mechanical switching and lineage specification.

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 stiff scaffold, either reversible or irreversible activation of the osteogenic markers was observed with different 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] Specifically, 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 specifications.[41] The actin-actin bonding and polarity of depolymerization under cyclic force were also critical in transducing the temporal mechanical effect on stem cell differentiation.[42] Conjunctionally, substrate stiffness-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 modifications, 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 differentiation lineage by controlling the accessibility of the genome.[46]

In addition, the duration of cell culture was considered to influence the dynamic changes of mechanically regulated differentiation. Specifically, 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 differentiation potency would be preserved regarding mechanical memory is amidst ongoing arguments.[49] Together, the mechanical imprints alter subsequent lineage specifications of MSCs.

  Type of Force and Mechanoreceptors Top

To appreciate the mechanical effect 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, defined 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 differentiation.[50] In addition, oscillatory shear stress was exhibited to alter the organization of F-actin and orchestrate β-catenin to determine lineage specification.[51] For example, fibronectin as the ligand of focal adhesions was proposed to participate in ossification. Anthrax toxin receptor 1 (Antxr1) was recently identified 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 ossification.[53] Other significant classifications included stretching force. In line with the circumferential direction of the tubal surface, the resulting strain was proposed to facilitate the differentiation 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 differentiation. 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 influencing the migration of dental pulp-derived MSCs.[56] Moreover, Piezo1 was suggested to influence MSC differentiation 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 differentiation thereof. Intertwined with the downstream BMP2/Smad/Runx2/Osterix axis, TRPM7 was displayed to perceive intermittent fluid 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 influx 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 baroreflex, 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 reflex.[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 significant since compromised baroreflex 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 fluid shear stress and altered local vascular resistance. Specifically, GPR68 responds to extracellular acidosis and activates either the phospholipase C formation and the calcium flux 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 deficiency in GPR68 prevented flow-induced vasodilation.[68] Together, these studies highlighted how the mechanical effect affects fluid dynamics. Furthermore, whether these mechanoreceptors play similar roles in stem cells or other types of cells is worth further investigation.

  Mechanotransduction and Cardiovascular Implications Top

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 inflammation, the quiescent resident fibroblasts would be induced for lineage specification toward myofibroblasts and thereby accumulate collagen and excessively produce focal adhesion.[70] Enhanced mechanical burden stiffens the myocardium, which eventually brings about scarring. Conversely, the rigidified substrate also promoted the migration and differentiation of fibroblasts. The Hippo pathway involving YAP/TAZ was considered relevant to the mechanotransduction, as demonstrated by a murine cell line.[71] Stiffened extracellular matrix further deteriorated cardiac pumping functions and eventually led to heart failure.
Table 2: Mechanotransduction of stem cells correlates with the pathogenesis of cardiovascular diseases

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Another aspect regarding the mechanical effect on cardiac function is valvular physiology. Embryological studies suggested that the regurgitant flow promoted the recruitment of endocardial cells, the morphogenesis of valve leaflets, 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 calcification 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 identified specific 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 stiff 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 filaments 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 effects 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 flow 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 influx 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 flow.[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 exemplified by the injury of the abdominal aorta, MSCs were demonstrated to migrate from adjacent intact intima and subsequently differentiated 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. Exemplified by recapitulating ischemic heart disease, priming MSCs with oxidative stress was demonstrated to facilitate engraftment and cardiogenic differentiation. 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 Top

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 of motor clutch demonstrates the effect exerted through matrix rigidity upon force transmission.[85] Besides, to confer the confounding mechanical input and for precise quantification 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 differentiation. Employing the tension sensor of Förster resonance energy transfer to define the force gradient[89] and further to the assessment at the single-molecule level[90] are advanced illustrations reflecting the industrial evolvement of experimental apparatus to analyze mechanotransduction. These advancements propelled a more accurate appraisal of MSCs' physiology and differentiative behaviors.

On the clinical end, the frontier for MSC mechanotransduction addressed the translation in cardiovascular applications. Aside from previous experience in other fields, the advanced understanding of the physical stimuli inspired interest in how hemodynamics affects 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 flow 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 flow condition differently altered the actin filament organization of MSCs.[92] Recognition of such mechanotransduction propels the manufacturing of artificial 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 Top

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 differentiate into cardiomyocytes and other lineages. Preclinical studies have interrogated the efficacy 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 benefit 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 efficacy.

Another modality of MSC therapeutics is to manipulate the local residing stem cells. Although with limited differentiation potential, those stem cells located at the vascular wall were demonstrated to contribute to cardiomyocyte formation. Hypothetically, the intima senses the vascular shear flow 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] Effective 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 efficacy and safety of such treatments.

  Conclusions Top

Mechanotransduction plays an important role in MSC phenotype and differentiation. 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 specification. Furthermore, “time” is also a crucial component as the previous cultural condition is imprinted as mechanical memory and thereby influences subsequent fate commitments. Understanding how to tune the differentiation and stemness properties of MSCs mechanically will help us to better define the cellular quality for clinical application. Different 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-filament, and in conjunction with biochemical stimuli, the mechanical stimuli alter cellular physiology. In the cardiovascular system, the versatile mechanosensing is reflected in stretch-sensitive ion channels Piezo1/Piezo2 and Tentonin 3 in baroreflex, as well as shear flow-sensitive GPR68 in small-diameter vessels. As for clinical implications, the observation of mechanical effects 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 final manuscript.

Financial support and sponsorship

The authors received financial support for research purposes from the National Science and Technology 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 financial relationships that could be construed as a potential conflict of interest.

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