Involvement of urokinase receptor in the cross-talk between human hematopoietic stem cells and bone marrow microenvironment

// Carmine Selleri 1, * , Nunzia Montuori 2, * , Annamaria Salvati 3 , Bianca Serio 1 , Ada Pesapane 2 , Patrizia Ricci 1 , Anna Gorrasi 3 , Anna Li Santi 3 , Gunilla Hoyer-Hansen 4 , Pia Ragno 3 1 Department of Medicine and Surgery, University of Salerno, Salerno, Italy 2 Department of Translational Medical Sciences, “Federico II” University, Naples, Italy 3 Department of Chemistry and Biology, University of Salerno, Salerno, Italy 4 The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark * These authors have contributed equally to this work Correspondence to: Pia Ragno, email: pragno@unisa.it Keywords: urokinase receptor, uPAR, hematopoietic stem cells, bone marrow microenvironment, leukemia Received: January 04, 2016 Accepted: July 18, 2016 Published: August 08, 2016 ABSTRACT Hematopoietic stem cells (HSCs) reside in bone marrow (BM) and can be induced to mobilize into the circulation for transplantation. Homing and lodgement into BM of transplanted HSCs are the first critical steps in their engraftment and involve multiple interactions between HSCs and the BM microenvironment. uPAR is a three domain receptor (DIDIIDIII) which binds urokinase, vitronectin, integrins. uPAR can be cleaved and shed from the cell surface generating full-length and cleaved soluble forms (suPAR and DIIDIII-suPAR). DIIDIII-suPAR can bind fMLF receptors through the SRSRY sequence (residues 88-92). We previously reported the involvement of soluble uPAR in HSC mobilization. We now investigate its possible role in HSC homing and engraftment. We show similar levels of circulating full-length suPAR in healthy donors and in acute myeloid leukemia (AML) patients before and after the pre-transplant conditioning regimen. By contrast, levels of circulating DIIDIII-suPAR in AML patients are higher as compared to controls and significantly decrease after the conditioning. We found that suPAR and uPAR 84-95 , a uPAR-derived peptide which mimics active DIIDIII-suPAR, induce a significant increase in Long Term Culture (LTC)-Initiating Cells (ICs) and in the release of clonogenic progenitors from LTCs of CD34 + HSCs. Further, suPAR increases adhesion and survival of CD34 + KG1 AML cells, whereas uPAR 84-95 increases their proliferation. Thus, circulating DIIDIII-suPAR, strongly increased in HSC mobilization, is indeed down-regulated by pre-transplant conditioning, probably to favour HSC homing. BM full-length suPAR and DIIDIII-suPAR may be involved in HSC lodgement within the BM by contributing to a suitable microenvironment.