Biomedical subjects

R Mohle

Publications and source records attributed to R Mohle.

3 recordsLinked to original sources

PubMed1999

Stromal derived factor-1-induced chemokinesis of cord blood CD34(+) cells (long-term culture-initiating cells) through endothelial cells is mediated by E-selectin.

Homing of hematopoietic stem cells to the bone marrow (BM) involves sequential interaction with adhesion molecules expressed on BM endothelium (BMEC) and chemokine stromal derived factor-1 (SDF-1). However, the mechanism whereby adhesion molecules regulate the SDF-1-induced transendothelial migration process is not known. E-selectin is an endothelial-specific selectin that is constitutively expressed by the BMEC in vivo. Hence, we hypothesized that E-selectin may mediate SDF-1-induced transendothelial migration of CD34(+) cells. We show that CD34(+) cells express both E-selectin ligand and fucosyltransferase-VII (FucT-VII). Soluble E-selectin-IgG chimera binds avidly to 75% +/- 10% of CD34(+) cells composed mostly of progenitors and cells with long-term culture-initiating cell (LTC-IC) potential. To assess the functional capacity of E-selectin to mediate CD34(+) cell migration in a transendothelial migration system, CD34(+) cells were placed on transwell plates coated with interleukin-1beta-activated BMEC. In the absence of SDF-1, there was spontaneous migration of 7.0% +/- 1.4% of CD34(+) cells and 14.1% +/- 2.2% of LTC-IC. SDF-1 induced migration of an additional 23.0% +/- 4.4% of CD34(+) cells and 17.6% +/- 3.6% of LTC-IC. Blocking MoAb to E-selectin inhibited SDF-1-induced migration of CD34(+) cells by 42.0% +/- 2.5% and LTC-IC by 90.9% +/- 16.6%. To define the mechanism of constitutive expression of E-selectin by the BMEC in vivo, we have found that vascular endothelial growth factor (VEGF(165)) induces E-selectin expression by cultured endothelial cells. VEGF-stimulated endothelial cells support transendothelial migration of CD34(+) cells that could be blocked by MoAb to E-selectin. These results suggest that trafficking of subsets of CD34(+) cells with LTC-IC potential is determined in part by sequential interactions with E-selectin and SDF-1.

Cell Communication↗

PubMed1998

Evidence for circulating bone marrow-derived endothelial cells.

It has been proposed that hematopoietic and endothelial cells are derived from a common cell, the hemangioblast. In this study, we demonstrate that a subset of CD34(+) cells have the capacity to differentiate into endothelial cells in vitro in the presence of basic fibroblast growth factor, insulin-like growth factor-1, and vascular endothelial growth factor. These differentiated endothelial cells are CD34(+), stain for von Willebrand factor (vWF), and incorporate acetylated low-density lipoprotein (LDL). This suggests the possible existence of a bone marrow-derived precursor endothelial cell. To demonstrate this phenomenon in vivo, we used a canine bone marrow transplantation model, in which the marrow cells from the donor and recipient are genetically distinct. Between 6 to 8 months after transplantation, a Dacron graft, made impervious to prevent capillary ingrowth from the surrounding perigraft tissue, was implanted in the descending thoracic aorta. After 12 weeks, the graft was retrieved, and cells with endothelial morphology were identified by silver nitrate staining. Using the di(CA)n and tetranucleotide (GAAA)n repeat polymorphisms to distinguish between the donor and recipient DNA, we observed that only donor alleles were detected in DNA from positively stained cells on the impervious Dacron graft. These results strongly suggest that a subset of CD34+ cells localized in the bone marrow can be mobilized to the peripheral circulation and can colonize endothelial flow surfaces of vascular prostheses.

Animals↗

PubMed1997

Regulation of hematopoiesis by microvascular endothelium.

The bone marrow microenvironment is a complex three dimensional structure where hematopoietic stem cells proliferate, mature, migrate into the sinusoidal space, and enter the circulation in an exquisitely regulated fashion. Stromal cells within the BM microenvironment provide a suitable environment for self-renewal, proliferation and differentiation of hematopoietic stem cells. Within the hematopoietic microenvironment, whether it is embryonic yolk sac, fetal liver, or adult bone marrow, microvascular endothelium not only acts as a gatekeeper controlling the trafficking and homing of hematopoietic progenitors, but also provides cellular contact and secretes cytokines that allows for the preservation of the steady state hematopoiesis. Recently, homogenous monolayers of bone marrow endothelial cells (BMEC) have been isolated and cultivated in tissue culture. Long-term coculture studies have shown that BMEC monolayers are unique type of endothelium and can support long-term proliferation of hematopoietic progenitor cells particularly megakaryocytic and myeloid progenitor cells by constitutive elaboration of lineage-specific cytokines such as G-CSF, GM-CSF, M-CSF, Kit-ligand, IL6, FLK-2 ligand, and leukemia inhibitory factor. Direct cellular contact between hematopoietic progenitor cells and BMEC monolayers through specific adhesion molecules including beta1, beta2 integrins and selectins play a critical role in trafficking and possibly proliferation of hematopoietic stem cells. Dysfunction of microvascular endothelial cells within the hematopoietic microenvironment may result in stem cell disorders and progression to aplastic anemias, and contribute to graft failure during bone marrow transplantation. Further studies on the role of microvascular endothelium in the regulation of hematopoietic stem cell homing and proliferation may enhance our understanding of the pathophysiology of stem cell and leukemic disorders.

Antigens, CD34↗