Signaling Molecules Induced by cAMP and the Mechanical Environment On MSC Morphology and Function

Stem cells residing in tissue-specific niches that contain the necessary cues for differentiation can regenerate tissue upon injury or disease. Before stem cells can realize their therapeutic promise as a cell source for the clinical regeneration of aged, injured, and disease tissues, several challenges must be overcome. Specifically, to control the fate of stem cells, one must understand the intertwined roles of internal cues (e.g., genes, proteins) and external cues (e.g., biochemical (soluble) factors, matrix elasticity and anisotropy) in determining the fate of stem cells, and in particular, the signaling imparted. Understanding the signaling processes that will enhance the maturation of stem cell cultures for cell replacement therapies, and in particular stem cell-derived neurons, could facilitate the development of novel therapies for treating diseases such as Alzheimer’s and Parkinson’s diseases. Towards this challenge, the overall goal of this study is to elucidate the interaction between soluble factors (namely, the induction of cyclic adenosine monophosphate, cAMP) and mechanical properties (matrix elasticity and anisotropy) in mediating cell fate decision, that is associated with both function and morphology. A critical step in neuronal development is the formation of axon/ dendrite polarity. Recent studies in cortical and hippocampal neurons have shown that local elevation of cAMP and protein kinase A (PKA) activity is a critical early event in axon initiation, to promote axon differentiation and growth. However, we found cAMP, a soluble cue used either alone or in combination with other factors to induce neural differentiation of MSCs, promoted neural function but produced only transient neural-like morphology. In contrast, low modulus surfaces produced neural-like morphology but the cells were not functional. In this study we identified signaling molecules, i.e. SMURF1, regulated by CREB1 (which is activated by cAMP) that could be modulating maturation of MSCs to the neuronal phenotype, both function and morphology. We will discuss how mechanical stimuli, anisotropy in addition to modulus, affect or cross-talk with the signaling imparted by cAMP to affect differentiation.