Hematopoietic stem cell regeneration through paracrine regulation of the Wnt5a/Prox1 signaling axis

• Published in: The Journal of clinical investigation Vol. 132; no. 12; pp. 1 - 13
• Main Authors: Lin, Qiqi, Wu, Limei, Chatla, Srinivas, Chowdhury, Fabliha A, Atale, Neha, Joseph, Jonathan, Du, Wei
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.06.2022
• Subjects: Aging; Anemia; Binding sites; Biomedical research; Bone marrow; Cell biology; Cellular signal transduction; CXCL12 protein; Fanconi syndrome; Genetic aspects; Health aspects; Hematology; Hematopoietic stem cells; Leukemia; Microenvironments; Paracrine signalling; Pax2 protein; Phenotypes; Physiological aspects; Radiation; Regeneration (Biology); Stem cell research; Stem cell transplantation; Stem cells; Stromal cells; Transcription factors; Wnt protein; Wnt proteins; United States; Hematology; Hematopoietic stem cells; Cell Biology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI155914

The crosstalk between the BM microenvironment (niche) and hematopoietic stem cells (HSCs) is critical for HSC regeneration. Here, we show that in mice, deletion of the Fanconi anemia (FA) genes Fanca and Fancc dampened HSC regeneration through direct effects on HSCs and indirect effects on BM niche cells. FA HSCs showed persistent upregulation of the Wnt target Prox1 in response to total body irradiation (TBI). Accordingly, lineage-specific deletion of Prox1 improved long-term repopulation of the irradiated FA HSCs. Forced expression of Prox1 in WT HSCs mimicked the defective repopulation phenotype of FA HSCs. WT mice but not FA mice showed significant induction by TBI of BM stromal Wnt5a protein. Mechanistically, FA proteins regulated stromal Wnt5a expression, possibly through modulating the Wnt5a transcription activator Pax2. Wnt5a treatment of irradiated FA mice enhanced HSC regeneration. Conversely, Wnt5a neutralization inhibited HSC regeneration after TBI. Wnt5a secreted by LepR+CXCL12+ BM stromal cells inhibited β-catenin accumulation, thereby repressing Prox1 transcription in irradiated HSCs. The detrimental effect of deregulated Wnt5a/Prox1 signaling on HSC regeneration was also observed in patients with FA and aged mice. Irradiation induced upregulation of Prox1 in the HSCs of aged mice, and deletion of Prox1 in aged HSCs improved HSC regeneration. Treatment of aged mice with Wnt5a enhanced hematopoietic repopulation. Collectively, these findings identified the paracrine Wnt5a/Prox1 signaling axis as a regulator of HSC regeneration under conditions of injury and aging.