Stromal pleiotrophin regulates repopulation behavior of hematopoietic stem cells

Pleiotrophin (Ptn) is strongly expressed by stromal cells which maintain hematopoietic stem cells (HSC). However, in vivo, Ptn deficiency does not alter steady-state hematopoiesis. On the other hand, knockdown of Ptn (PtnKD) in stromal cells increases production of hematopoietic progenitors as well as HSC activity in co-cultures, suggesting that Ptn may have a role in HSC activation. Indeed, transplantations of wild-type (WT, Ptn+/+) HSC into Ptn-/- mice show increased donor cell production in serial transplantations and dominant myeloid regeneration caused by Ptn-dependent regulation of HSC repopulation behavior. This regulation of LSK function is associated with increased proliferation, and, on a molecular level, with upregulated expression of cyclin D1 ( Ccnd1 ) and C/EBPa ( Cepba ), but reduced of PPARγ ( Pparg ). The known HSC regulator β-catenin is, however, not altered in the absence of Ptn. In conclusion, our results point to different Ptn-mediated regulatory mechanisms in normal hemostasis and in hematopoietic regeneration and in maintaining the balance of myeloid and lymphoid regeneration. Moreover, our results support the idea that microenvironmental Ptn regulates hematopoietic regeneration through β-catenin-independent regulation of Ccnd1 and Cebpa.