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Stem cell fate decisions are informed by physical and chemical cues presented within and by the extracellular matrix. Despite the generally attributed importance of extracellular cues in governing self-renewal, differentiation, and collective behavior, knowledge gaps persist with regard to the individual, synergistic, and competing effects that specific physiochemical signals have on cell function. To better understand basic stem cell biology, as well as to expand opportunities in regenerative medicine and tissue engineering, a growing suite of customizable biomaterials has been developed. These next-generation cell culture materials offer user-defined biochemical and biomechanical properties, increasingly in a manner that can be controlled in time and 3D space. This review highlights recent innovations in this regard, focusing on advances to culture and maintain stemness, direct fate, and to detect stem cell function using biomaterial-based strategies. 

Abstract Although mechanical signals presented by the extracellular matrix are known to regulate many essential cell functions, the specific effects of these interactions, particularly in response to dynamic and heterogeneous cues, remain largely unknown. Here, a modular semisynthetic approach is introduced to create protein–polymer hydrogel biomaterials that undergo reversible stiffening in response to user‐specified inputs. Employing a novel dual‐chemoenzymatic modification strategy, fusion protein‐based gel crosslinkers are created that exhibit stimuli‐dependent intramolecular association. Linkers based on calmodulin yield calcium‐sensitive materials, while those containing the photosensitive light, oxygen, and voltage sensing domain 2 (LOV2) protein give phototunable constructs whose moduli can be cycled on demand with spatiotemporal control about living cells. These unique materials are exploited to demonstrate the significant role that cyclic mechanical loading plays on fibroblast‐to‐myofibroblast transdifferentiation in 3D space. The moduli‐switchable materials should prove useful for studies in mechanobiology, providing new avenues to probe and direct matrix‐driven changes in 4D cell physiology.