Biochemical factors can help reprogram somatic cells into pluripotent stem cells, yet the role of biophysical factors during reprogramming is unknown. Here, we show that biophysical cues, in the form of parallel microgrooves on the surface of cell-adhesive substrates, can replace the effects of small-molecule epigenetic modifiers and significantly improve reprogramming efficiency. The mechanism relies on the mechanomodulation of the cells' epigenetic state. Specifically, decreased histone deacetylase activity and upregulation of the expression of WD repeat domain 5 (WDR5)--a subunit of H3 methyltranferase--by microgrooved surfaces lead to increased histone H3 acetylation and methylation. We also show that microtopography promotes a mesenchymal-to-epithelial transition in adult fibroblasts. Nanofibrous scaffolds with aligned fibre orientation produce effects similar to those produced by microgrooves, suggesting that changes in cell morphology may be responsible for modulation of the epigenetic state. These findings have important implications in cell biology and in the optimization of biomaterials for cell-engineering applications.

Myelinating Schwann cells (SCs) are highly plastic cells that are able to dedifferentiate and re-enter the cell cycle. However, the molecular signals controlling dedifferentiation are not completely understood. Because a connection between mitogenic signaling and myelin loss has been suggested, we investigated the role of cAMP, a strong inducer of the myelinating phenotype, and mitogenic factors activating receptor tyrosine kinases (RTKs) on SC dedifferentiation. We herein provide evidence indicating that cAMP was required to not only initiate but also maintain a state of differentiation because SCs rapidly dedifferentiated and became competent to resume proliferation upon the removal of cAMP stimulation. Surprisingly, isolated SCs could undergo multiple cycles of differentiation and dedifferentiation upon cAMP addition and removal, respectively, in the absence of mitogenic factors and without entering the cell cycle. Conversely, the activation of RTKs and the ERK cascade by a variety of growth factors, including neuregulin, was not sufficient to initiate dedifferentiation in the presence of cAMP. Importantly, a reduction of cAMP triggered dedifferentiation through a mechanism that required JNK, rather than ERK, activity and an induction of the expression of c-Jun, a transcriptional inhibitor of myelination. In summary, the reversible transition from an undifferentiated to a myelinating state was dependent on cAMP but independent of RTK signaling and cell cycle progression, further indicating that dedifferentiation and proliferation are uncoupled and differentially regulated events in SCs.

Cell reprogramming is a revolutionized biotechnology that offers a powerful tool to engineer cell fate and function for regenerative medicine, disease modeling, drug discovery, and beyond. Leveraging advances in biomaterials and micro/ nanotechnologies can enhance the reprogramming performance in vitro and in vivo through the development of delivery strategies and the control of biophysical and biochemical cues. In this review, we present an overview of the state-of-the-art technologies for cell reprogramming and highlight the recent breakthroughs in engineering biomaterials with micro/nanotechnologies to improve reprogramming efficiency and quality. Finally, we discuss future directions and challenges for reprogramming technologies and clinical translation.

Adipocytes were engineered for local delivery of anticancer therapeutics, including fatty acid and small-molecule drug. The lipolysis triggered by tumor cells promoted the release of these anticancer therapeutics. In addition, the immunogenic tumor phenotype induced by anticancer fatty acid combined with tumor-responsive doxorubicin prodrug enhanced cancer therapy.

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Cell reprogramming has wide applications in tissue regeneration, disease modeling and personalized medicine, but low reprogramming efficiency remains a challenge. In addition to biochemical cues, biophysical factors can modulate the epigenetic state and a variety of cell functions. However, how biophysical factors help overcome the epigenetic barrier for cell reprogramming are not well understood. Here we utilized microfluidic channels to induce a transient deformation of the cell nucleus, which caused the disassembly of the nuclear lamina and a downregulation of DNA methylation and histone (H3K9) for 12-24 hours. These global decreases of heterochromatin marks at the early stage of cell reprogramming strikingly enhanced the conversion of fibroblasts into neurons and induced pluripotent stem cells. Consistently, inhibition of DNA methylation and H3K9 methylation partially mimicked the effects of mechanical squeezing on iN reprogramming efficiency. Knocking down lamin A had similar effects to squeezing on enhancing the reprogramming efficiency. Based on these findings, we developed a scalable microfluidic system that enabled a continuous cell processing to effectively prime the epigenetic state for cell reprogramming, demonstrating the potential of mechano-biotechnology for cell

Cross-linked polyacrylamide hydrogels are commonly used in biotechnology and cell culture applications due to advantageous properties, such as the precise control of material stiffness and the attachment of cell adhesive ligands. However, the chemical and physical properties of polyacrylamide gels cannot be altered once fabricated. Here, we develop a photodegradable polyacrylamide gel system that allows for a dynamic control of polyacrylamide gel stiffness with exposure to light. Photodegradable polyacrylamide hydrogel networks are produced by copolymerizing acrylamide and a photocleavable ortho-nitrobenzyl (o-NB) bis-acrylate cross-linker. When the hydrogels are exposed to light, the o-NB cross-links cleave and the stiffness of the photodegradable polyacrylamide gels decreases. Further examination of the effect of dynamic stiffness changes on cell behavior reveals that in situ softening of the culture substrate leads to changes in cell behavior that are not observed when cells are cultured on presoftened gels, indicating that both dynamic and static mechanical environments influence cell fate. Notably, we observe significant changes in nuclear localization of YAP and cytoskeletal organization after in situ softening; these changes further depend on the type and concentration of cell adhesive proteins attached to the gel surface. By incorporating the simplicity and well-established protocols of standard polyacrylamide gel fabrication with the dynamic control of photodegradable systems, we can enhance the capability of polyacrylamide gels, thereby enabling cell biologists and engineers to study more complex cellular behaviors that were previously inaccessible using regular polyacrylamide gels.

Muscle loss and impairment resulting from traumatic injury can be alleviated by therapies using muscle stem cells. However, harvesting sufficient numbers of autologous myogenic stem cells and expanding them efficiently has been challenging. Here, we show that myogenic stem cells (predominantly Pax7 + cells) selectively expanded from readily obtainable dermal fibroblasts or Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#termsReprints and permissions information is available at www.nature.com/reprints.