Work

Systemic Administration Of Pleiotrophin Induces Hematopoietic Stem Cell (HSC) Regeneration in vivo

Year: 2010

Type: article

Abstract: The elucidation of bone marrow microenvironmental signals which promote HSC regeneration in vivo would have important implications for the treatment of patients undergoing radiation therapy, chemotherapy and stem cell transplantation. We recently reported that pleiotrophin, a soluble heparin-binding growth factor, induced a 10-fold expansion of long-term repopulating HSCs in culture (Himburg et al. Blood, Nov 2008; 112: 78). Based on this observation, we hypothesized that PTN might also be a regenerative growth factor for HSCs. Here we tested the effect of systemic administration of PTN to mice to determine if PTN could promote HSC regeneration in vivo following total body irradiation (TBI). C57Bl6 mice were irradiated with 700 cGy followed by intraperitoneal administration of 2 μg PTN or saline × 7 days, followed by analysis of BM stem and progenitor cell content. Saline-treated mice demonstrated a significant reduction in total BM cells, BM c-kit+sca-1+lin- (KSL) cells, colony forming cells (CFCs) and long term culture-initiating cells (LTC-ICs) compared to non-irradiated mice. Irradiated, PTN-treated mice demonstrated a 2.3-fold increase in total BM cells (p=0.03), a 5.6-fold increase in BM KSL stem/progenitor cells (p=0.04), a 2.9-fold increase in BM CFCs (p=0.004) and an 11-fold increase in LTC-ICs (p=0.03) compared to irradiated, saline-treated mice. Moreover, competitive repopulating assays demonstrated that BM from irradiated, PTN-treated mice contained 5-fold increased competitive repopulating units (CRUs) compared to irradiated, saline-treated mice (p=0.04). Taken together, these data demonstrate that the administration of PTN induces BM HSC and progenitor cell regeneration in vivo following injury. To determine whether PTN acted directly on BM HSCs to induce their proliferation and expansion in vivo, mice ingested BrDU × 7 days and compared BrDU incorporation in BM KSL cells in saline-treated versus PTN-treated mice. PTN-treated mice demonstrated a significant increase in BrDU+ BM KSL cells compared to saline-treated controls (p=0.04). PTN is a novel, secreted growth factor for BM HSCs and induces their regeneration in vivo while preserving their repopulating capacity. PTN has therapeutic potential as a growth factor to accelerate hematopoietic reconstitution in vivo in patients undergoing myelosuppressive radiotherapy or chemotherapy.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2009.12.110