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

Carmine Selleri,Nunzia Montuori,Pia Ragno,Anna Gorrasi,Anna Li Santi,Bianca Serio,Gunilla Hoyer-Hansen,Ada Pesapane,Annamaria Salvati,Patrizia Ricci

doi:10.18632/oncotarget.11115

Carmine Selleri, Nunzia Montuori + Show 8 more

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https://doi.org/10.18632/oncotarget.11115

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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 uPAR84-95, 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 uPAR84-95 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.

Highlights

Hematopoietic stem cells (HSCs) are clonogenic cells capable of self-renewal and multilineage differentiation
We found that suPAR and uPAR84-95, 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
We characterized the presence of the different forms of uPAR and of its extracellular ligands, uPA and VN, in bone marrow (BM) stroma; we examined the effects of soluble uPAR forms in long term cultures of CD34+ HSCs and on the KG1 cell line, as a model for CD34+ hematopoietic cells [14]

Summary

Introduction

Hematopoietic stem cells (HSCs) are clonogenic cells capable of self-renewal and multilineage differentiation. The expression of the CD34 antigen and lineage negativity are commonly used in clinics to identify human HSCs. The majority of HSCs resides in the bone marrow (BM), which provides them with a suitable microenvironment, regulating their proliferation/survival and differentiation [1,2]. HSCs are retained in the BM mainly by their adhesive interactions with the cellular and matrix components of the stroma and by interaction with specific BM chemokines, in particular the stromal-derived factor 1 (SDF1), through the CXCR4 receptor [1,2]. Mobilized peripheral blood (PB) HSCs represent the major source of stem cells for autologous stem cell transplantion (SCT); they are increasingly used in allogeneic SCT, because of the relative ease of collection, the higher yield of stem cells and the shorter time to engraftment. The most common mobilizer is the granulocyte-colony stimulating factor (G-CSF) [3,4]

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