Associate Professor University of Pittsburgh Medical Center P, PA, United States
Abstract: Bone marrow (BM) microenvironment comprises various types of cell populations, including endosteal and sinusoidal endothelial cells, mesenchymal stromal cells (MSCs), and osteoblast lineage cells, which support hematopoietic stem cell (HSC) maintenance through direct interactions or paracrine factors secreted by the niche cells. Transcription factor PROX1 (Prospero-related homeodomain transcription factor 1), is known to play critical functions in a variety of tissues including the lens, heart, liver, pancreas and central nervous system (CNS). We previously identified a new paracrine Wnt5a/Prox1 axis as a regulator of HSC regeneration under conditions of injury and aging. Here we investigate role of PROX1 in BM microenvironment using mesenchymal specific Prox1 conditional knockout mouse model (Prox1f/fPrx1Cre), and found that mice deficient for Prox1 in the BM niche are hypersensitive to 5-FU challenge. Loss of Prox1 in the BM affects MSC differentiation under stressed conditions, and consequently compromises their hematopoiesis supportive function both in vitro and in vivo. Untargeted cytokine profiling reveals a significantly reduced levels of activin receptor-like kinase 1 (ALK1) in the BM of Prox1f/fPrx1Cre mice compared to that in the control Prox1f/f mice. Recombinant ALK1 treatment mimics Prox1f/fPrx1Cre phenotypes in the wild-type (WT) mice. Conversely, activation of ALK1 signaling pathway rescues MSC defects in Prox1-knockout mice. Taken together, our results uncovered a previously unknown function of transcription factor PROX1 in the BM microenvironment and provide novel insights on targeting PROX1 and its downstream signaling pathways to improve BM function in mice.
Funding Source: This work is supported by R01HL151390, R56HL169348, R01CA285400 to W.D., and a Children’s Leukemia Research Association Research Grant (to W.D). This project used the Hillman Animal Facility, supported in part, by NIH P30CA047904.
