Biology subjects

Tierney, M. T.

Publications and source records attributed to Tierney, M. T..

3 recordsLinked to original sources

bioRxiv2026

A commensally regulated immune rheostat fine-tunes skin barrier fitness

At the skins surface, the epidermis must balance stem cell renewal with barrier maintenance to withstand environmental stress and shield against pathogens. Here, we identify a microbial-immune-epithelial feedback mechanism that integrates environmental information into stem cell regulation. Specifically, we show that Langerhans cells--an intra-epithelial macrophage population-- orchestrate this circuit by producing prostaglandin E2, which restrains stem cell proliferation, promotes epidermal differentiation and maintains barrier integrity during homeostasis. Upon pathway disruption, stem cells become overactivated, impairing differentiation and compromising barrier function. Upstream, Langerhans cell activity is tuned by the local microbial environment in a rheostat-like fashion, coupling commensal sensing to stem cell control. Our findings provide a general framework for how barrier tissues achieve adaptive homeostasis amid continual external challenge.

immunology↗

bioRxiv2024

Modulation of the JAK2-STAT3 pathway promotes expansion and maturation of human iPSCs-derived myogenic progenitor cells

Generation of in vitro induced pluripotent cells (hiPSCs)-derived skeletal muscle progenitor cells (SMPCs) holds great promise for regenerative medicine for skeletal muscle wasting diseases, as for example Duchenne Muscular Dystrophy (DMD). Multiple approaches, involving ectopic expression of key regulatory myogenic genes or small molecules cocktails, have been described by different groups to obtain SMPC towards cell-transplantation in vivo as a therapeutic approach to skeletal muscle diseases. However, hiPSCs-derived SMPC generated using transgene-free protocols are usually obtained in a low amount and resemble a more embryonal/fetal stage of differentiation. Here we demonstrate that modulation of the JAK2/STAT3 signaling pathway during an in vitro skeletal muscle differentiation protocol, increases the yield of PAX7+ and CD54+ SMPCs and drive them to a post- natal maturation stage, in both human ES and patient-derived iPSCs. Importantly, upon removal of the inhibition from the cultures, the obtained SMPCs are able to differentiate into multinucleated myotubes in vitro. These findings reveal that modulation of the JAK2/STAT3 signaling pathway is a potential therapeutic avenue to generate SMPCs in vitro with increase potential for cell-therapy approaches.

cell biology↗

bioRxiv2023

Stem cells tightly regulate dead cell clearance to maintain tissue fitness

Summary ParagraphMacrophages and dendritic cells have long been appreciated for their ability to migrate to and engulf dying cells and debris, including some of the billions of cells that are naturally eliminated from our body daily. However, a substantial number of these dying cells are cleared by non-professional phagocytes, local epithelial cells that are critical to organismal fitness. How non-professional phagocytes sense and digest nearby apoptotic corpses while still performing their normal tissue functions is unclear. Here, we explore the molecular mechanisms underlying their multifunctionality. Exploiting the cyclical bouts of tissue regeneration and degeneration during the hair cycle, we show that stem cells can transiently become non-professional phagocytes when confronted with dying cells. Adoption of this phagocytic state requires both local lipids produced by apoptotic corpses to activate RXR, and tissue-specific retinoids for RAR{gamma} activation. This dual factor dependency enables tight regulation of the genes requisite to activate phagocytic apoptotic clearance. The tunable phagocytic program we describe here offers an effective mechanism to offset phagocytic duties against the primary stem cell function of replenishing differentiated cells to preserve tissue integrity during homeostasis. Our findings have broad implications for other non-motile stem or progenitor cells which experience cell death in an immune-privileged niche.

cell biology↗