Distinct Bone Marrow Sources of Pleiotrophin Control Hematopoietic Stem Cell Maintenance and Regeneration

Bone marrow (BM) perivascular stromal cells and vascular endothelial cells (ECs) are essential for hematopoietic stem cell (HSC) maintenance, but the roles of distinct niche compartments during HSC regeneration are less understood. Here we show that Leptin receptor-expressing (LepR+) BM stromal cells and ECs dichotomously regulate HSC maintenance and regeneration via secretion of pleiotrophin (PTN). BM stromal cells are the key source of PTN during steady-state hematopoiesis because its deletion from stromal cells, but not hematopoietic cells, osteoblasts, or ECs, depletes the HSC pool. Following myelosuppressive irradiation, PTN expression is increased in bone marrow endothelial cells (BMECs), and PTN+ ECs are more frequent in the niche. Moreover, deleting Ptn from ECs impairs HSC regeneration whereas Ptn deletion from BM stromal cells does not. These findings reveal dichotomous and complementary regulation of HSC maintenance and regeneration by BM stromal cells and ECs. [Display omitted] •PTN secretion by BM stromal cells is essential for HSC maintenance•Hematologic recovery following irradiation requires PTN from BM stromal cells and ECs•PTN secretion by BMECs is essential for HSC regeneration following irradiation•Irradiation enriches for PTN-expressing BMECs in the niche Himburg et al. demonstrate dichotomous regulation of blood stem cell maintenance and regeneration by BM stromal cells and ECs. Utilizing conditional genetic models, the authors show that blood stem cell maintenance requires PTN secretion by BM stromal cells, whereas blood stem cell regeneration requires complementary PTN production by BMECs.