Biology subjects

Kim, Y. L.

Publications and source records attributed to Kim, Y. L..

3 recordsLinked to original sources

bioRxiv2025

Rejuvenation-Responsive and Senolytic-Sensitive Muscle Stem Cells Unveiled by CD200 and CD63 in Geriatric Muscle

Muscle stem cells (MuSCs) are parenchymal cells in skeletal muscle regeneration and maintenance. With aging, MuSCs experience a decline in their regenerative function and reduction in their number. However, recent evidence points to substantial heterogeneity within the aged MuSC population, raising questions about the underlying mechanisms of age-associated dysfunction. Here, we used Pax7CreERT2;RosaYFP mice (MuSCYFP) to label Pax7-expressing MuSCs and chronologically traced MuSCs until geriatric age. Genetic labeling and chronological tracing revealed that the number of YFP+ MuSC remained comparable between young, middle and geriatric ages. At geriatric age, YFP+ MuSCs exhibited reduced expression of traditional MuSC markers such as VCAM1 and PAX7. A previously unrecognized subpopulation emerged, characterized by loss of VCAM1 and low or absent PAX7. Despite their altered marker profile, these cells retained transcriptional signatures of quiescence and myogenic potential, but displayed significantly reduced proliferative and regenerative capacities. They displayed gene expression patterns indicative of senescence-like state and were selectively ablated by senolytic treatment. DHT restored regenerative function in aged mice and re-induced VCAM1 expression in YFP+/Pax7-/low/VCAM1- cells, indicating responsiveness to rejuvenation. Based on their emergence with aging, functional impairment and responsiveness to rejuvenation, we termed this population GERI-MuSCs (Geriatric Emerging Rejuvenation-responsive and Impaired MuSCs). CD63 and CD200 were identified as novel surface markers that together with VCAM1, reliably detect GERI-MuSCs as well as classical Pax7+/VCAM1High MuSCs, providing a tool for comprehensive isolation of MuSCs from aged wild-type mice. Together, our findings provide a refined framework for studying MuSC aging and offer new tools for isolating functionally distinct MuSC subsets from aged skeletal muscle.

developmental biology↗

bioRxiv2024

Muscle-resident mesenchymal progenitors sense and repair peripheral nerve injury via the GDNF-BDNF axis

Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal progenitors that can contribute to muscle tissue homeostasis and regeneration, as well as postnatal maturation and lifelong maintenance of the neuromuscular system. Recently, traumatic injury to the peripheral nerve was shown to activate FAPs, suggesting that FAPs can respond to nerve injury. However, questions of how FAPs can sense the anatomically distant peripheral nerve injury and whether FAPs can directly contribute to nerve regeneration remained unanswered. Here, utilizing single-cell transcriptomics and mouse models, we discovered that a subset of FAPs expressing GDNF receptors Ret and Gfra1 can respond to peripheral nerve injury by sensing GDNF secreted by Schwann cells. Upon GDNF sensing, this subset becomes activated and expresses Bdnf. FAP-specific inactivation of Bdnf (Prrx1Cre; Bdnffl/fl) resulted in delayed nerve regeneration owing to defective remyelination, indicating that GDNF-sensing FAPs play an important role in the remyelination process during peripheral nerve regeneration. In aged mice, significantly reduced Bdnf expression in FAPs was observed upon nerve injury, suggesting the clinical relevance of FAP-derived BDNF in the age-related delays in nerve regeneration. Collectively, our study revealed the previously unidentified role of FAPs in peripheral nerve regeneration, and the molecular mechanism behind FAPs response to peripheral nerve injury.

neuroscience↗

bioRxiv2020

Epigenetic transcriptional reprogramming by WT1 mediates a repair response during podocyte injury

In the context of human disease, the mechanisms whereby transcription factors reprogram gene expression in response to injury are not well understood. This is particularly true in kidney podocytes, injury to which is the common and initial event in many processes that lead End Stage Kidney Disease. WT1 is a master regulator of gene expression in podocytes, binding nearly all genes known to be crucial for maintenance of the glomerular filtration barrier. Here, using purified populations of podocytes and glomeruli, we investigated WT1-mediated transcriptional reprogramming during the course of podocyte injury. Using the Adriamycin murine model of Focal Segmental Glomerulosclerosis, we discovered that podocyte injury led to increased intensity of WT1 binding and to the acquisition of new WT1 binding sites, both at previously identified target genes and at newly bound target genes, providing mechanistic insight on the transcriptional response to injury. We also observed a previously unrecognized transient increase in expression of WT1 target genes in both mice and human kidney organoids. Together, these features appear to constitute an attempt to repair the glomerular filtration barrier after podocyte injury. At later stages of injury, when proteinuria became severe, there was greatly decreased WT1 binding to most target genes. Furthermore, WT1 appeared to be required to maintain active chromatin marks at its target genes. These active marks were converted to repressive marks after loss of WT1 or Adriamycin-induced injury. This response to injury suggests that there may be a potential window of opportunity for repairing podocyte injury as a treatment for glomerular disease in humans.

molecular biology↗