Biology subjects

Yang, B. A.

Publications and source records attributed to Yang, B. A..

3 recordsLinked to original sources

bioRxiv2022

Three-dimensional chromatin re-organization during muscle stem cell aging

Age-related skeletal muscle atrophy or sarcopenia is a significant societal problem that is becoming amplified as the worlds population continues to increase. A critical contributor to sarcopenia is the loss in the number and function of muscle stem cells, which maintain tissue homeostasis and regenerate damage. The molecular mechanisms that govern muscle stem cell aging encompass changes across multiple regulatory layers and are integrated by the three-dimensional organization of the genome. To quantitatively understand how hierarchical chromatin architecture changes during muscle stem cell aging, we generated 3D chromatin conformation maps (Hi-C) and integrated these datasets with multi-omic (chromatin accessibility and transcriptome) profiles from bulk populations and single cells. We observed that muscle stem cells display static behavior at global scales of chromatin organization during aging and extensive rewiring of local contacts at finer scales that were associated with variations in transcription factor binding and aberrant gene expression. These data provide insights into genome topology as a regulator of molecular function in stem cell aging.

cell biology↗

bioRxiv2021

Neutrophil and natural killer cell imbalances prevent muscle stem cell mediated regeneration following murine volumetric muscle loss

Volumetric muscle loss (VML) overwhelms the innate regenerative capacity of mammalian skeletal muscle (SkM), leading to numerous disabilities and reduced quality of life. Immune cells are critical responders to muscle injury and guide tissue resident stem cell and progenitor mediated myogenic repair. However, how immune cell infiltration and inter-cellular communication networks with muscle stem cells are altered following VML and drive pathological outcomes remains underexplored. Herein, we contrast the cellular and molecular mechanisms of VML injuries that result in fibrotic degeneration or regeneration of SkM. Following degenerative VML injuries, we observe heightened infiltration of natural killer (NK) cells as well as persistence of neutrophils beyond two weeks post injury. Functional validation of NK cells revealed an antagonistic role on neutrophil accumulation in part via inducing apoptosis and CCR1 mediated chemotaxis. The persistent infiltration of neutrophils in degenerative VML injuries was found to contribute to impairments in muscle stem cell regenerative function, which was also attenuated by transforming growth factor beta 1 (TGF{beta}1). Blocking TGF{beta} signaling reduced neutrophil accumulation and fibrosis, as well as improved muscle specific force. Collectively, these results enhance our understanding of immune cell-stem cell crosstalk that drives regenerative dysfunction and provide further insight into possible avenues for fibrotic therapy exploration. SINGLE SENTENCE SUMMARYComparison of muscle injuries resulting in regeneration or fibrosis reveals inter-cellular communication between neutrophils and natural killer cells impacts muscle stem cell mediated repair.

cell biology↗

bioRxiv2020

Sestrins regulate age-induced deterioration of muscle stem cell homeostasis

The health and homeostasis of skeletal muscle is preserved by a population of tissue resident stem cells called satellite cells. Young healthy satellite cells maintain a state of quiescence, but aging or metabolic insults results in reduced capacity to prevent premature activation and stem cell exhaustion. As such, understanding genes and pathways that protect satellite cell maintenance of quiescence are needed. Sestrins are a class of stress-inducible proteins that act as antioxidants and inhibit the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Despite these pivotal roles, the role of Sestrins has not been explored in adult stem cells. Herein, we show that Sestrin1,2 loss results in hyperactivation of the mTORC1 complex, increased propensity to enter the cell cycle and shifts in metabolic flux. Aging of Sestrin1,2 knockout mice demonstrated a loss of MuSCs and reduced ability to regenerate. These findings demonstrate Sestrins function to help maintain MuSC metabolism that supports quiescence and against aging. HighlightsO_LISestrin deficiency alters mTORC1 signaling in muscle stem cells (MuSCs). C_LIO_LIIn young mice, Sestrins are dispensable for regenerative responses of MuSCs. C_LIO_LISestrin deficiency accelerates age-dependent loss and dysfunction of MuSCs. C_LI

cell biology↗