Human Pluripotent Stem Cell Mechanobiology: Manipulating the Biophysical Microenvironment for Regenerative Medicine and Tissue Engineering Applications

A stem cell in its microenvironment is subjected to a myriad of soluble chemical cues and mechanical forces that act in concert to orchestrate cell fate. Intuitively, many of these soluble and biophysical factors have been the focus of intense study to successfully influence and direct cell differentiation in vitro. Human pluripotent stem cells (hPSCs) have been of considerable interest in these studies due to their great promise for regenerative medicine. Culturing and directing differentiation of hPSCs, however, is currently extremely labor‐intensive and lacks the efficiency required to generate large populations of clinical‐grade cells. Improved efficiency may come from efforts to understand how the cell biophysical signals can complement biochemical signals to regulate cell pluripotency and direct differentiation. In this concise review, we explore hPSC mechanobiology and how the hPSC biophysical microenvironment can be manipulated to maintain and differentiate hPSCs into functional cell types for regenerative medicine and tissue engineering applications. Stem Cells 2015;33:3187–3196

[1]  S. Mitalipov,et al.  Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer , 2013, Cell.

[2]  Athanasios Mantalaris,et al.  The benefit of human embryonic stem cell encapsulation for prolonged feeder-free maintenance. , 2008, Biomaterials.

[3]  H. Moses,et al.  Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. , 2001, Molecular biology of the cell.

[4]  M Cristina Marchetti,et al.  Scaling of traction forces with the size of cohesive cell colonies. , 2011, Physical review letters.

[5]  R. Derynck,et al.  TGF-β family signaling in stem cells. , 2013, Biochimica et biophysica acta.

[6]  Albert J. Keung,et al.  Soft microenvironments promote the early neurogenic differentiation but not self-renewal of human pluripotent stem cells. , 2012, Integrative biology : quantitative biosciences from nano to macro.

[7]  V. Tabar,et al.  Pluripotent stem cells in regenerative medicine: challenges and recent progress , 2014, Nature Reviews Genetics.

[8]  Hossein Baharvand,et al.  Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. , 2006, The International journal of developmental biology.

[9]  David J. Mooney,et al.  Harnessing Traction-Mediated Manipulation of the Cell-Matrix Interface to Control Stem Cell Fate , 2010, Nature materials.

[10]  A. Moore,et al.  Elasticity of human embryonic stem cells as determined by atomic force microscopy. , 2011, Journal of biomechanical engineering.

[11]  Yoshiki Sasai,et al.  Molecular pathway and cell state responsible for dissociation-induced apoptosis in human pluripotent stem cells. , 2010, Cell stem cell.

[12]  Jianping Fu,et al.  Forcing stem cells to behave: a biophysical perspective of the cellular microenvironment. , 2012, Annual review of biophysics.

[13]  Lotte Markert,et al.  Identification of distinct topographical surface microstructures favoring either undifferentiated expansion or differentiation of murine embryonic stem cells. , 2009, Stem cells and development.

[14]  Jianping Fu,et al.  Hippo/YAP-mediated rigidity-dependent motor neuron differentiation of human pluripotent stem cells , 2014, Nature materials.

[15]  Dong Ryul Lee,et al.  Human somatic cell nuclear transfer using adult cells. , 2014, Cell stem cell.

[16]  Wesley R. Legant,et al.  Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels , 2013, Nature materials.

[17]  Daniel G. Anderson,et al.  The influence of scaffold elasticity on germ layer specification of human embryonic stem cells. , 2011, Biomaterials.

[18]  Jerry C. Hu,et al.  Mechanical characterization of differentiated human embryonic stem cells. , 2009, Journal of biomechanical engineering.

[19]  Vasan Venugopalan,et al.  High-throughput optical screening of cellular mechanotransduction , 2014, Nature Photonics.

[20]  J. Ando,et al.  Differentiation from embryonic stem cells to vascular wall cells under in vitro pulsatile flow loading , 2005, Journal of Artificial Organs.

[21]  Yarong Liu,et al.  Synthetic niches for differentiation of human embryonic stem cells bypassing embryoid body formation. , 2014, Journal of biomedical materials research. Part B, Applied biomaterials.

[22]  Peter W Zandstra,et al.  Niche‐mediated control of human embryonic stem cell self‐renewal and differentiation , 2007, The EMBO journal.

[23]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[24]  D. Melton,et al.  Generation of Functional Human Pancreatic β Cells In Vitro , 2014, Cell.

[25]  N. Sato,et al.  The Rho-Rock-Myosin Signaling Axis Determines Cell-Cell Integrity of Self-Renewing Pluripotent Stem Cells , 2008, PloS one.

[26]  R. McKay,et al.  New cell lines from mouse epiblast share defining features with human embryonic stem cells , 2007, Nature.

[27]  J. Itskovitz‐Eldor,et al.  Differentiation of human embryonic stem cells on three-dimensional polymer scaffolds , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Trotter,et al.  Derivation of pluripotent epiblast stem cells from mammalian embryos , 2007, Nature.

[29]  T. Cao,et al.  Short periods of cyclic mechanical strain enhance triple-supplement directed osteogenesis and bone nodule formation by human embryonic stem cells in vitro. , 2013, Tissue engineering. Part A.

[30]  Thomas Boudou,et al.  A hitchhiker's guide to mechanobiology. , 2011, Developmental cell.

[31]  A. Bishop,et al.  Embryonic stem cells , 2004, Cell proliferation.

[32]  Robert Langer,et al.  Hyaluronic acid hydrogel for controlled self-renewal and differentiation of human embryonic stem cells , 2007, Proceedings of the National Academy of Sciences.

[33]  David M Reynolds,et al.  Signaling network crosstalk in human pluripotent cells: a Smad2/3-regulated switch that controls the balance between self-renewal and differentiation. , 2012, Cell stem cell.

[34]  Kimiko Yamamoto,et al.  Fluid shear stress induces differentiation of Flk-1-positive embryonic stem cells into vascular endothelial cells in vitro. , 2005, American journal of physiology. Heart and circulatory physiology.

[35]  D. Schaffer,et al.  Biophysical regulation of epigenetic state and cell reprogramming. , 2013, Nature materials.

[36]  Lifeng Chi,et al.  Topographic effect on human induced pluripotent stem cells differentiation towards neuronal lineage. , 2013, Biomaterials.

[37]  Yohei Hayashi,et al.  Integrins Regulate Mouse Embryonic Stem Cell Self‐Renewal , 2007, Stem cells.

[38]  D. Leckband,et al.  Integrated biochemical and mechanical signals regulate multifaceted human embryonic stem cell functions , 2010, The Journal of cell biology.

[39]  Yu Sun,et al.  Microfabricated arrays for high-throughput screening of cellular response to cyclic substrate deformation. , 2010, Lab on a chip.

[40]  M. Capogrossi,et al.  Epigenetic histone modification and cardiovascular lineage programming in mouse embryonic stem cells exposed to laminar shear stress. , 2006, Circulation research.

[41]  M. Gharib,et al.  Carbon nanotube-based substrates for modulation of human pluripotent stem cell fate. , 2014, Biomaterials.

[42]  M. Lutolf,et al.  Artificial niche microarrays for probing single stem cell fate in high throughput , 2011, Nature Methods.

[43]  Robert Langer,et al.  Three-dimensional biomaterials for the study of human pluripotent stem cells , 2011, Nature Methods.

[44]  Jason A Burdick,et al.  Neurotrophin-induced differentiation of human embryonic stem cells on three-dimensional polymeric scaffolds. , 2005, Tissue engineering.

[45]  Rong Fan,et al.  Nanotopography influences adhesion, spreading, and self-renewal of human embryonic stem cells. , 2012, ACS nano.

[46]  A. Yee,et al.  Expression of Oct4 in human embryonic stem cells is dependent on nanotopographical configuration. , 2013, Acta biomaterialia.

[47]  Stephen A. Morin,et al.  Glycosaminoglycan-binding hydrogels enable mechanical control of human pluripotent stem cell self-renewal. , 2012, ACS nano.

[48]  Donald E Ingber,et al.  Mechanical control of tissue morphogenesis during embryological development. , 2006, The International journal of developmental biology.

[49]  M. Sheetz,et al.  Force-dependent cell signaling in stem cell differentiation , 2012, Stem Cell Research & Therapy.

[50]  Dennis E. Discher,et al.  Physical plasticity of the nucleus in stem cell differentiation , 2007, Proceedings of the National Academy of Sciences.

[51]  Vamsi K Yadavalli,et al.  Effect of substrate stiffness on early human embryonic stem cell differentiation , 2013, Journal of Biological Engineering.

[52]  Michael P. Sheetz,et al.  Appreciating force and shape — the rise of mechanotransduction in cell biology , 2014, Nature Reviews Molecular Cell Biology.

[53]  R. Nerem,et al.  Fluid shear stress promotes an endothelial-like phenotype during the early differentiation of embryonic stem cells. , 2010, Tissue engineering. Part A.

[54]  F. Prinz,et al.  Elastic properties of induced pluripotent stem cells. , 2011, Tissue engineering. Part A.

[55]  K. Shakesheff,et al.  Combined hydrogels that switch human pluripotent stem cells from self-renewal to differentiation , 2014, Proceedings of the National Academy of Sciences.

[56]  Ning Wang,et al.  Force via integrins but not E-cadherin decreases Oct3/4 expression in embryonic stem cells. , 2011, Biochemical and biophysical research communications.

[57]  Viola Vogel,et al.  Cell fate regulation by coupling mechanical cycles to biochemical signaling pathways. , 2009, Current opinion in cell biology.

[58]  C. Hamanishi,et al.  Mechanical stimulation of cyclic tensile strain induces reduction of pluripotent related gene expressions via activation of Rho/ROCK and subsequent decreasing of AKT phosphorylation in human induced pluripotent stem cells. , 2012, Biochemical and biophysical research communications.

[59]  Bernadette Ateghang,et al.  Embryonic stem cells utilize reactive oxygen species as transducers of mechanical strain‐induced cardiovascular differentiation , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[60]  Laurie B. Hazeltine,et al.  Temporal impact of substrate mechanics on differentiation of human embryonic stem cells to cardiomyocytes. , 2014, Acta biomaterialia.

[61]  Chad A. Cowan,et al.  The Src Family of Tyrosine Kinases Is Important for Embryonic Stem Cell Self-renewal* , 2004, Journal of Biological Chemistry.

[62]  M. Krieg,et al.  Tensile forces govern germ-layer organization in zebrafish , 2008, Nature Cell Biology.

[63]  S. Levenberg,et al.  Tensile forces applied on a cell-embedded three-dimensional scaffold can direct early differentiation of embryonic stem cells toward the mesoderm germ layer. , 2015, Tissue engineering. Part A.

[64]  A. Stieg,et al.  Rigid microenvironments promote cardiac differentiation of mouse and human embryonic stem cells , 2013, Science and technology of advanced materials.

[65]  J. Ando,et al.  Cyclic strain induces mouse embryonic stem cell differentiation into vascular smooth muscle cells by activating PDGF receptor beta. , 2008, Journal of applied physiology.

[66]  S. Kyrylenko,et al.  Adaptation to Robust Monolayer Expansion Produces Human Pluripotent Stem Cells With Improved Viability , 2013, Stem cells translational medicine.

[67]  E. Kumacheva,et al.  Micropatterning of human embryonic stem cells dissects the mesoderm and endoderm lineages. , 2009, Stem cell research.

[68]  M. Sheetz,et al.  Local force and geometry sensing regulate cell functions , 2006, Nature Reviews Molecular Cell Biology.

[69]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2007, Cell.

[70]  J. Elisseeff,et al.  Derivation of Chondrogenically-Committed Cells from Human Embryonic Cells for Cartilage Tissue Regeneration , 2008, PloS one.

[71]  J. D. de Pablo,et al.  TGFbeta/Activin/Nodal pathway in inhibition of human embryonic stem cell differentiation by mechanical strain. , 2008, Biophysical journal.

[72]  Keesung Kim,et al.  Direct differentiation of human embryonic stem cells into selective neurons on nanoscale ridge/groove pattern arrays. , 2010, Biomaterials.

[73]  G. Daley,et al.  Human embryonic stem cells , 2004, Bone Marrow Transplantation.

[74]  Juan J de Pablo,et al.  Inhibition of human embryonic stem cell differentiation by mechanical strain , 2006, Journal of cellular physiology.

[75]  S. Gerecht,et al.  The Differential Formation of the LINC-Mediated Perinuclear Actin Cap in Pluripotent and Somatic Cells , 2012, PloS one.

[76]  Donald E Ingber,et al.  Micromechanical control of cell and tissue development: implications for tissue engineering. , 2007, Advanced drug delivery reviews.

[77]  K. Narayanan,et al.  Extracellular Matrix-Mediated Differentiation of Human Embryonic Stem Cells: Differentiation to Insulin-Secreting Beta Cells , 2014 .

[78]  Gordana Vunjak-Novakovic,et al.  Bioactive hydrogel scaffolds for controllable vascular differentiation of human embryonic stem cells. , 2007, Biomaterials.

[79]  E. Dufresne,et al.  Cadherin-based intercellular adhesions organize epithelial cell–matrix traction forces , 2012, Proceedings of the National Academy of Sciences.

[80]  Raymond H. W. Lam,et al.  Mechanics Regulates Fate Decisions of Human Embryonic Stem Cells , 2012, PloS one.

[81]  Li Yang,et al.  Biophysical regulation of histone acetylation in mesenchymal stem cells. , 2011, Biophysical journal.

[82]  B. Snel,et al.  Tyrosine Phosphorylation Profiling in FGF-2 Stimulated Human Embryonic Stem Cells , 2011, PloS one.

[83]  Antonella Farsetti,et al.  Epigenetic Histone Modification and Cardiovascular Lineage Programming in Mouse Embryonic Stem Cells Exposed to Laminar Shear Stress , 2005 .

[84]  Ning Wang,et al.  Soft Substrates Promote Homogeneous Self-Renewal of Embryonic Stem Cells via Downregulating Cell-Matrix Tractions , 2010, PloS one.

[85]  Daniel J Hoeppner,et al.  Non-colony type monolayer culture of human embryonic stem cells. , 2012, Stem cell research.

[86]  Shulan Tian,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[87]  J. Thomson,et al.  Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells , 2004, Nature Biotechnology.

[88]  Hong Yee Low,et al.  Substrate topography and size determine the fate of human embryonic stem cells to neuronal or glial lineage. , 2013, Acta biomaterialia.