Role of stromal‐derived factor‐1 in the hematopoietic‐supporting activity of human mesenchymal stem cells

Abstract

Mesenchymal stem cells (MSC) have the ability to support and maintain hematopoiesis in vitro. However, mechanisms implicated in this support are not fully characterized. In the present study, the role of stromal-derived factor-1 (SDF-1)/CXCR4 axis in the interactions between MSC and hematopoietic stem/progenitor cells (HSPC) was studied. Human bone marrow MSC were plated as feeder layers in Dexter-type long-term cultures (LTC) with human cord blood CD34(+) HSPC. Cultures were supplemented weekly with neutralizing antibodies against CXCR4 or SDF-1 for 5 wk. LTC-initiating cell (IC) activity was strongly dependent on the SDF-1/CXCR4 axis, as both antibodies significantly decreased secondary colony-forming cell production. To assess the effect of SDF-1/CXCR4 axis on progenitor cell proliferation, LTC-IC killing assays were carried out: in LTC of CD34(+) cells in contact with MSC, treatment with anti-CXCR4 antibody significantly reduced the number of cycling progenitors. These results indicate that the SDF-1/CXCR4 axis promotes HSPC proliferation in contact with MSC. Interestingly, when HSPC were separated from MSC by a semipermeable membrane, LTC-IC activity became CXCR4 independent. Multiplex analysis of MSC-conditioned medium revealed that in addition to SDF-1, MSC produced stimulatory and inhibitory factors, such as interleukin (IL)-6, IL-11, granulocyte macrophage-colony stimulating factor as well as monocyte-chemoattractant protein-1. Altogether, human MSC support hematopoiesis in Dexter-type cultures through the activation of the SDF-1/CXCR4 axis. Our data further suggest that SDF-1 stimulates retention of HSPC in MSC niches which expose them to stimulatory and inhibitory factors in a paracrine manner.

Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium

“…Besides their migratory role, these CXCR4 positive MSCs participated in neovascularization and differentiated into new myocytes. In addition, MSCs secrete or express SDF-1α [34,35] and its interaction with CXCR4 increases survival of progenitor cells [6]. SDF-1α could serve as an adhesive molecule by binding CXCR4-expressing cells to the vessel wall [36], which is consistent with our study that a high degree of CXCR4 expression is observed in the vascular endothelial cells.…”

Distinctive contact between CD34+ hematopoietic progenitors and CXCL12+ CD271+ mesenchymal stromal cells in benign and myelodysplastic bone marrow

“…CXCL12 signaling has been shown to regulate the balance between quiescence, cell cycle entry and apoptosis in CD34 þ hematopoietic stem cells, 48,49 and to promote cell cycle progression in CD34 þ HSPCs 50 in a contact-dependent manner in vitro. 7 Strong CXCL12 expression by CD271 þ ALP þ MSCs could be a source of abnormal survival/proliferation signaling for adjacent neoplastic CD34 þ HSPCs. CXCL12 is also involved in hematopoietic stem cell homing, 27 and isolated CD34 þ HSPCs from MDS patients are impaired in their ability to migrate toward CXCL12, 51 a finding that is associated with increased susceptibility to apoptosis in vitro.…”

“…MSCs are of particular interest because they are capable of supporting self-renewing proliferation of CD34 þ hematopoietic progenitors. [5][6][7] Those purified MSCs that show multipotency are called …”

“…MSCs are of particular interest because they are capable of supporting self-renewing proliferation of CD34 þ hematopoietic progenitors. [5][6][7] Those purified MSCs that show multipotency are called mesenchymal stem cells, 8 or osteoprogenitors when they demonstrate capability of reconstituting bone in vivo. 9 In our study we aimed to quantitatively and comprehensively map the normal MSC component of intact bone marrow to allow for identification of derangements of MSCs in myeloid neoplasia, particularly in MDS.…”

Hematopoietic Microenvironment in the Fetal Liver: Roles of Different Cell Populations

“…Apparently, the role of these cells is not limited to their differentiation into more specialized components of the hematopoietic stroma. It has been shown for bone marrow MSCs that they can produce stromal cell-derived factor-1 [70], interact with hematopoietic cells via surface molecules (VCAM-1, cadherins, integrins and, etc. ), and regulate their proliferation and differentiation by secreting wide range of cytokines [71,72].…”