SFRP1 and SFRP2 jointly regulate normal and malignant hematopoietic progenitors by influencing mesenchymal cells in the hematopoietic niche

Secreted frizzled-related proteins (SFRPs) are secreted proteins identified as antagonists of the Wnt signaling pathway. Sfrp1 or Sfrp2 deletion in mice attenuates the hematopoietic stem/progenitor cell (HSPC) pool; however, the mechanisms by which SFRP1/2 support hematopoietic cells remain unclear. Here, we showed that SFRP1/2 functions as a niche factor for both normal and malignant HSPCs by acting on mesenchymal stromal cells (MSCs). Addition of SFRP1/2-blocking antibodies to a co-culture of OP-9 MSCs and normal mouse bone marrow hematopoietic cells reduced the long-term culture-initiating cell number. Addition of these antibodies to the co-culture of MSCs and MB-1 myeloblastoma cells reduced the cobblestone area, which is a characteristic feature of leukemic stem cells. During co-culture with MB-1 cells, these antibodies upregulated the target genes of the Wnt and bone morphogenetic protein pathways in OP-9 MSCs, but not in MB-1 cells. Additionally, addition of blocking antibodies to OP-9 MSC monoculture attenuated cell growth. Overall, our findings suggest that SFRP1 and SFRP2 maintain normal and malignant HSPC functions in the hematopoietic niche by modulating the Wnt and bone morphogenetic protein pathways in MSCs.