SP/drug efflux functionality of hematopoietic progenitors is controlled by mesenchymal niche through VLA-4/CD44 axis

Abstract

Hematopoiesis is orchestrated by interactions between hematopoietic stem/progenitor cells (HSPCs) and stromal cells within bone marrow (BM) niches. Side population (SP) functionality is a major characteristic of HSPCs related to quiescence and resistance to drugs and environmental stresses. At steady state, SP cells are mainly present in the BM and are mostly absent from the circulation except in stress conditions, raising the hypothesis of the versatility of the SP functionality. However, the mechanism of SP phenotype regulation is unclear. Here we show for the first time that the SP functionality can be induced in lin(-) cells from unmobilized peripheral blood after nesting on mesenchymal stromal cells (MSCs). This MSC-induced SP fraction contains HSPCs as demonstrated by their (i) CD34(+) cell percentage, (ii) quiescent status, (iii) in vitro proliferative and clonogenic potential, (iv) engraftment in NSG (NOD SCID gamma chain) mice and (v) stemness gene expression profile. We demonstrate that SP phenotype acquisition/reactivation by circulating lin(-) cells is dependent on interactions with MSCs through VLA-4/α4β1-integrin and CD44. A similar integrin-dependent mechanism of SP phenotype acquisition in acute myeloid leukemia circulating blasts suggests an extrinsic regulation of ATP-binding cassette-transporter activity that could be of importance for a better understanding of adhesion-mediated chemoresistance mechanisms.

Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications

“…We first demonstrated their in vitro potential to support long-term culture-initiating cell cultures (47) and their capability to maintain primitive hematopoietic progenitor cells, as a higher number of hematopoietic colonies was detected after 5 weeks of coculture compared with cultures without NHO-MSC support ( Figure 3E). NHO-MSCs were also capable of inducing the SP phenotype of Lin -cells from peripheral blood ( Figure 3F), as recently described with BM-MSCs (48). SP cells were CD45 + CD34 + , confirming their hematopoietic origin.…”

“…In that respect, it is interesting to note that CXCL12 levels are increased in NHO patient plasma (Supplemental Figure 6) and that CXCL12's expression has been reported to be stimulated by OSM in MSCs (68). Beside their capacity for AOC differentiation, human NHO-MSCs exhibit similar molecular and functional characteristics to BM-MSCs in terms of long-term human hematopoiesis support and SP functionality induction in vitro (48). More importantly, when seeded on hydroxyapatite scaffolds and sorted from naive C57BL/6 mice were cultured for 10 days in control medium, osteogenic medium, or osteogenic medium plus mouse OSM (25 ng/ml).…”

“…In the present study, we show that human NHOs represent a suitable microenvironment for maintaining quiescent HSCs and determining their activation state and fate, therefore meeting the definition of HSC niches. Indeed, we show that CD34 + HSCs, with a quiescent SP phenotype (45,48,62) and the ability to reconstitute human hematopoiesis in vivo when injected in immunodeficient mice, dwell in human NHOs. It is likely that these NHO-resident HSCs come from the circulation and home to NHO using a suitable mesenchymal and endothelial microenvironment (niches) similar to that existing in the BM.…”

The truncated RUNX1/ETO activates VLA-4-dependent adhesion and migration of hematopoietic progenitor cells

“…Accordingly, as reported recently, VLA-4 and CD44, which is also up-regulated by RUNX1/ETO, 9 contribute to side population functionality of hematopoietic progenitor cells co-cultured with mesenchymal stromal cells. 10 Taken together our data reveal a direct link between RUNX1/ETO and integrin VLA-4 expression and VLA-4-mediated adhesion and migration capabilities, which might play an important role in RUNX1/ETO-induced AML development. The inducible knockdown of VLA-4 subunits in de novo developing RUNX1/ETOtr triggered AML in mice might uncover a role of VLA-4 for the function of RUNX1/ETOtr during leukemia development.…”

GATA2 regulates differentiation of bone marrow-derived mesenchymal stem cells

“…63 Furthermore, CD44 promotes the homing process between HSC and the hematopoietic niche through hyaluronic acid, which serves as a ligand. 64,65 Thus, GATA2 downregulation in patients with aplastic anemia may result in a decrease of extracellular matrix, similar to the functions of LAMB1 and CD44, resulting in impaired HSC support.…”