Search

Muscle stem cells (MuSCs) are specialized cells that reside in adult skeletal muscle poised to repair muscle tissue. The ability of MuSCs to regenerate damaged tissues declines markedly with aging and in diseases such as Duchenne muscular dystrophy, but the underlying causes of MuSC dysfunction remain poorly understood. Both aging and disease result in dramatic increases in the stiffness of the muscle tissue microenvironment from fibrosis. MuSCs are known to lose their regenerative potential if cultured on stiff plastic substrates. We sought to determine whether MuSCs harbor a memory of their past microenvironment and if it can be overcome. We tested MuSCs in situ using dynamic hydrogel biomaterials that soften or stiffen on demand in response to light and found that freshly isolated MuSCs develop a persistent memory of substrate stiffness characterized by loss of proliferative progenitors within the first three days of culture on stiff substrates. MuSCs cultured on soft hydrogels had altered cytoskeletal organization and activity of Rho and Rac guanosine triphosphate hydrolase (GTPase) and Yes-associated protein mechanotransduction pathways compared to those on stiff hydrogels. Pharmacologic inhibition identified RhoA activation as responsible for the mechanical memory phenotype, and single-cell RNA sequencing revealed a molecular signature of the mechanical memory. These studies highlight that microenvironmental stiffness regulates MuSC fate and leads to MuSC dysfunction that is not readily reversed by changing stiffness. Our results suggest that stiffness can be circumvented by targeting downstream signaling pathways to overcome stem cell dysfunction in aged and disease states with aberrant fibrotic tissue mechanics., Competing Interests: Competing interests statement:H.M.B. is a named inventor on patent applications held by Stanford University regarding prostaglandin signaling and muscle regeneration licensed to Epirium Bio. Y.X.W., C.A.H., and H.M.B. are named inventors on a patent application held by Stanford University for processing of multiplex microscopy images. H.M.B. is a cofounder of Myoforte Therapeutics, which was acquired by Epirium Bio, and receives consulting fees and has equity and stock options from Epirium Bio. C.M.M., S.S, X.S., F.J.B., G.W., and I.A.F. declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Triazole is frequently-used fungicide, which can leach into surface water through farmland and cause serious environmental pollution. Continuous exposure to triazole fungicides may cause harm to human health. Herein, β-cyclodextrin-polyacrylamide/covalent organic framework (β-CD-PAAM/TFPB-BD) hydrogel was fabricated at room temperature and used for the efficient removal of triazole fungicides. It displayed a short adsorption equilibrium time (50 min) and a total q e of 79.92 mg g−1. The adsorption process for triazole fungicides on β-CD-PAAM/TFPB-BD hydrogel conforms to the pseudo-second-order kinetic model and Freundlich model. The prepared hydrogel was recyclable and resistant to salt, high temperature, acid, and alkali. The reusability of fabricated sorbent can be achieved (i.e., five extraction cycles) for removal of target fungicides. Moreover, the β-CD-PAAM/TFPB-BD hydrogel was successfully applied to remove triazole fungicides in environmental water with removal efficiency ranging from 79.4% to 99.0%. [Display omitted] • β-cyclodextrin-polyacrylamide/covalent organic framework hydrogel was fabricated at room temperature. • The prepared hydrogel was recyclable and resistant to salt, high temperature, acid, and alkali. • Facile and efficient removal of triazole fungicides from environmental water. [ABSTRACT FROM AUTHOR]

[Display omitted] • Hydrogel has lower hardness and better safety. • HP-β-CD acts dual functions as hydrogel component and encapsulating resveratrol. • Hydrogel can increase anti-depressant effects of resveratrol. Thermosensitive Hydrogel System (THS) is a suitable candidate for targeted drug delivery, because of its intelligent response and controlled release. In this work, combination of guanidine-chitosan (GCS), β-glycerol phosphate disodium salt (β-GP) and hydroxypropyl-β-cyclodextrin (HP-β-CD) can successfully result in a novel THS by single factor and response surface method. The characterization of THS is detected with gelation temperature, FT-IR, SEM, in vitro release, rheology and biocompatibility. Resveratrol (Res) is selected as a model drug to evaluate the anti-depressant effects of THS loaded Res (Res-THS) via intranasal administration of chronic unpredictable mild stress (CUMS) rats. The results display that the Res-THS can increase concentration of neurotransmitter in rats' brain tissue via intranasal administration, indicating the anti-depressant effect. [ABSTRACT FROM AUTHOR]

Skeletal muscle stem cells (MuSCs) are essential for efficacious muscle repair, making MuSCs promising therapeutic targets for tissue engineering and regenerative medicine. MuSCs are presented with a diverse and temporally defined set of cues from their microenvironment during regeneration that direct stem cell expansion, differentiation, and return to quiescence. Understanding the complex interplay among these biophysical and biochemical cues is necessary to develop therapies targeting or employing MuSCs. To probe the role of mechanical cues presented by the extracellular matrix, we leverage chemically defined hydrogel substrates with controllable stiffness and adhesive ligand composition to characterize the MuSC response to matrix cues presented during early and late phases of regeneration. We demonstrate that relatively soft hydrogels recapitulating healthy muscle stiffness promote MuSC activation and expansion, while relatively stiff hydrogels impair MuSC proliferation and arrest myogenic progression. These effects are seen on soft and stiff hydrogels presenting laminin-111 and exacerbated on hydrogels presenting RGD adhesive peptides. Soluble factors present in the MuSC niche during different phases of regeneration, prostaglandin E2 and oncostatin M, synergize with matrix-presented cues to enhance stem cell expansion on soft substrates and block myogenic progression on stiff substrates. To determine if temporally varied matrix stiffness reminiscent of the regenerating microenvironment alters MuSC fate, we developed a photoresponsive hydrogel system with accelerated reaction kinetics that can be rapidly softened on demand. MuSCs cultured on these materials revealed that the cellular response to a stiff microenvironment is fixed within the first three days of culture, as subsequent softening back to a healthy stiffness did not rescue MuSC proliferation or myogenic progression. These results highlight the importance of temporally controlled biophysical and biochemical cues in regulating MuSC fate that can be harnessed to improve regenerative medicine approaches to restore skeletal muscle tissue. [ABSTRACT FROM AUTHOR]