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

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.

c-Kit M541L variant is related to ineffective hemopoiesis predisposing to clonal evolution in 3D in vitro biomimetic co-culture model of bone marrow niche

“…For example, umbilical cord-derived MSCs cultured in an alginate-gelatin bio-printed hydrogel scaffold show increased long-term viability and stemness maintenance compared to 2D monolayer cultures [ 40 , 41 ]. 3D co-cultures induce proliferation of CD34 + stem cells and increased expression of homing markers, such as C-X-C chemokine receptor type 4 (CXCR-4), the alpha-chemokine receptor for stromal-derived-factor-1 involved in HSC homing to the bone marrow and quiescence [ 21 , 42 ]. Indeed, CD34 + cells cultured in a 3D hydrogel system express higher levels of stemness markers and anchoring molecules, such as CD133, CXCR4 and N-Cadherin, with increased engraftment potential compared to those cells cultured in 2D standard conditions [ 18 ].…”

A novel oncogenic role for urokinase receptor in leukemia cells: molecular sponge for oncosuppressor microRNAs

“…A comparative analysis between peripheral blood and bone marrow (BM) AML blasts at diagnosis and relapse revealed that uPAR expression was significantly higher in circulating blast cells and at relapse, suggesting that uPAR expression positively correlates with invasive manifestations of AML [ 23 ]. Further, uPAR is involved in hematopoietic stem cell mobilization and in their cross-talk with the bone marrow microenvironment [ 24 – 25 ].…”

Multifaced Roles of the Urokinase System in the Regulation of Stem Cell Niches

“…HSCs obtained from transgenic uPAR -/mice and transplanted to wild-type splenectomized mice after radiation exposure (9.5 Gy) had reduced indicators of bone marrow integration and survival for REVIEWS a 2-week follow-up period compared to those of wildtype mouse HSCs. One of the potential molecular mechanisms of these effects may be the interaction of uPAR with integrins, in particular with α4β1-integrin that regulates migration and adhesion of HSCs to fibronectin and VCAM-1 during their homing and engraftment in the bone marrow [74][75][76][77][78]. The function of α4β1-integrin is known to depend on intact uPAR, because only the intact urokinase receptor interacts with integrins [79,80].…”