UNDERSTUDIED NICHE PLAYERS GOVERNING TISSUE-SPECIFIC PROGENITORS

Stem cells and progenitors are integral for tissue development, homeostasis and regeneration, and their dysfunction underlie development disorders, defective tissue regeneration, aging and cancer. In addition to intrinsic mechanisms, diverse niche cells influence stem/progenitor cell fate. Adult tissues harbor heterogenous stem/progenitor cell subsets which are intricately involved in tissue regeneration and disease. Yet, the fundamental cell types and molecular mechanisms that regulate distinct tissue-specific stem/progenitor cell populations remain poorly understood. Using the murine mammary gland as a model, we were the first to uncover primitive mesenchymal progenitor niche cells that have a remarkable capacity to contribute to a major subset of tissue-specific epithelial progenitors, indicating their potential role in replenishing progenitor cells central to tissue regeneration. We have also observed that sympathetic neurons modulate progenitor subsets in the niche and epithelium to orchestrate tissue regeneration. These niche cell types permeate diverse somatic tissues and thus, understanding their control of tissue-specific progenitors is critical for advancing progenitor- targeted therapies in regenerative medicine and malignancy. The proposed research will investigate how tissue-specific progenitor cell fate is dictated by mesenchymal progenitors and sympathetic neurons during adult tissue regeneration. We will utilize the postnatal mouse mammary gland as a tractable model to study tissue-specific progenitors given that it undergoes extensive morphogenesis directed by progenitors. We will explore niche cell-mediated modulation of progenitors and identify underlying molecular signals and mechanisms. We will employ a variety of strategies that include in vivo genetic reporter, lineage tracing and cell ablation mouse models and ex vivo organoids combined with phenotypic, functional assays and next-generation sequencing. Our findings will bridge key gaps in knowledge of the niche-driven circuitry that impacts tissue progenitors and provide a framework for improving the outcome of diseases attributed to aberrant progenitors. Project Number: 1R35GM162865-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Purna Joshi | Institution: UNIVERSITY OF TEXAS DALLAS, RICHARDSON, TX | Award Amount: $435,875 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award C Study Section[MRAC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11270943