OsteoblasticWntlessdeletion differentially regulates the fate and functions of bone marrow-derived stem cells in relation to age

Although functional association between Wnt signaling and bone homeostasis has been well described through genetic ablation ofWntless(Wls), the mechanisms of how osteoblasticWlsregulates the fate of bone marrow stromal cells (BMSCs) and hematopoietic stem cells (HSCs) in relation to age are not yet understood. Here, we generatedCol2.3-Cre;Wls(fl/fl)mice that were free from premature lethality and investigated age-related impacts of osteoblasticWlsdeficiency on hematopoiesis, BM microenvironment, and maintenance of BMSCs (also known as BM-derived mesenchymal stem/stromal cells) and HSCs. Ablation of osteoblasticWlsdeteriorated BM microenvironment and bone mass accrual along with age-independent effects on functions of BMSCs. OsteoblasticWlsdeletion impaired HSC repopulation and progeny with skewing toward myeloid lineage cells only at old stage. As proven by hallmarks of stem cell senescence, osteoblasticWlsablation differentially induced senescence of BMSCs and HSCs in relation to age without alteration in their BM frequency. Our findings support that deletion ofWlsinCol2.3-expressing cells induces senescence of BMSCs and impairs BM microenvironment in age-independent manner. Overall, long-term deterioration in BM microenvironment contributes to age-related HSC senescence with impaired progeny and hematopoiesis, which also suggests possible roles of osteoblasticWlson the maintenance of BM HSCs.

Automated summary

Deletion of osteoblastic Wls affects hematopoiesis, BM microenvironment, and BMSCs and HSCs maintenance, with age-dependent impacts. The deterioration in BM microenvironment contributes to age-related HSC senescence and impaired hematopoiesis, indicating potential roles of osteoblastic Wls in maintaining BM HSCs.