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Desirable properties such as hypoimmunogenicity, multipotency, and robust self-renewability have made adult stem cells an attractive cell source in regenerative medicine. [1][2][3][4] Nevertheless, ineffi cient and uncontrolled differentiation along defi ned lineages as well as a lack of understanding of the microenvironmental cues that bring about homeostatic regulation severely restrict their therapeutic applications. To realize the full potential of stem cells, determinative strategies to control their differentiation are required. To date, the most common approach relies heavily on the optimization of a complex mix of soluble cues such as growth factors, cytokines, and chemicals to direct lineage commitment. However, recent developments have shown that biophysical and biomechanical cues perceived by the stem cell within its niche can also function as potent regulators of stem cell fate. [ 5 , 6 ] Equipped with this knowledge and advances in micronanofabrication techniques, researchers are now able to reconstruct artifi cial ex vivo microenvironments which faithfully emulate native tissue niches to modulate a plethora of cellular behaviors. For instance, micro-nanoengineered physicochemical signals presented at the cell/substratum interface in the form of topologies, [7][8][9][10] matrix elasticity, [ 11 , 12 ] and even patterned extracellular matrix (ECM) proteins [13][14][15][16][17] have all been shown to signifi cantly impact stem cell response and differentiation. Central to this approach is the theme of biomimicry to recapitulate an in-vivo-like environment in order to mediate cell and tissue development. Although the use of such biomimetic surfaces has thus yielded some intriguing and promising results, little is known about the mechanotransduced responses at the molecular level. Elucidating the regulatory mechanistic cascades that direct stem cell response to these physicochemical cues with established signaling pathways may potentially allow new insights to be gained and bring about rational design of novel biomaterials for stem-cell-based engineering.Herein, we report a muscle-inspired micropatterned bioresorbable poly(lactide-co -glycolide) (PLGA) substrate confi guration that mimics the in vivo cell organization of the myocardium to bring about defi ned and exclusive myogenic differentiation of mesenchymal stem cells (MSCs) without any exogenously introduced soluble differentiation factor. We also identifi ed the focal adhesion kinase (FAK)mitogen-activated protein kinasekinase (MEK) pathway as potentially involved in this novel human MSC (hMSC) elongation-mediated myogenesis. This understanding of the engineered in vitro hMSC niche has highlighted the insuffi ciency of traditional over-simplifi ed culture systems and should yield novel strategies to infl uence stem cell fate.Effi cient transmission of both electrical and mechanical forces requires tight control over in vivo elongated myocytes' spatial anisotropic alignment and end-to-end coupling. To maintain essential structural and functional...