Disruption of Bis Leads to the Deterioration of the Vascular Niche for Hematopoietic Stem Cells

Abstract

The stem cell niche plays an important role in the microenvironmental regulation of hematopoietic stem cells, but the integration of niche activity remains poorly understood. In this study, we show that a functional deficiency of Bis/BAG‐3/CAIR‐1, a protein related to apoptosis and the response to cellular stress, results in perturbation of the vascular stem cell niche, causing a series of hematopoietic derangements. Mice with a targeted disruption of bis (bis−/−) exhibited a loss of hematopoietic stem cells and defective B‐cell development. However, this hematological defect of bis−/− mice was not reproduced when bis−/− bone marrow cells were transplanted into bis+/+ recipients. Moreover, bis+/+ bone marrow cells, when transplanted into bis−/− mice, reproduced the same defect as bis−/− cells, pointing to the microenvironmental origin of the phenotypes. Subsequent analysis of bis−/− mice bone marrow revealed a characteristic defect in the vascular stem cell niche that included the defective growth of stromal progenitor cells in colony forming unit‐fibroblasts, the defect in sinusoidal endothelium, and the loss of stromal cells expressing CXCL‐12 or IL‐7 in the bone marrow. In contrast, no abnormalities were observed in the growth and hematopoietic supporting activities of osteoblasts from bis−/− mice bone marrows. Collectively, these results indicate that Bis functions to mediate cellular regulation of the stem cell niche on the vascular compartment and suggest that the vascular and osteoblastic compartments of the stem cell niche can be independently regulated during the in vivo orchestration of hematopoiesis. STEM CELLS 2010;28:268–278

Concise Review: Multiple Niches for Hematopoietic Stem Cell Regulations

“…Mice, in which VEGFR2 is deleted [31], represent one such model, as described above. Of note, we recently identified another model, where a targeted disruption of Bis (Bcl-2-interacting cell death suppressor), a molecule implicated in the antiapoptotic or antistress response, caused the deterioration of the vascular niche [34,35]. Mutant mice (bis À/À ) exhibited early neonatal death and a series of hematological derangements that included the loss of B-cell lineages along with HSCs [34].…”

“…Of note, we recently identified another model, where a targeted disruption of Bis (Bcl-2-interacting cell death suppressor), a molecule implicated in the antiapoptotic or antistress response, caused the deterioration of the vascular niche [34,35]. Mutant mice (bis À/À ) exhibited early neonatal death and a series of hematological derangements that included the loss of B-cell lineages along with HSCs [34]. However, such defects were not observed when hematopoietic cells of mutant mice were transplanted into wild-type littermates, but the reciprocal transplantation of wild-type hematopoietic cells into bis À/À mice reproduced the phenotype, indicating microenvironmental origin of the phenotypes.…”

“…However, such defects were not observed when hematopoietic cells of mutant mice were transplanted into wild-type littermates, but the reciprocal transplantation of wild-type hematopoietic cells into bis À/À mice reproduced the phenotype, indicating microenvironmental origin of the phenotypes. The BM of mutant mice exhibited a marked loss of CAR cells and a decreased proliferation in vitro [34]. Moreover, the BM of bis À/À mice exhibited markedly dilated sinusoids, a decrease in capillary density and the loss of endothelial cells in the BM, thus demonstrating the association between the mesenchymal (reticular) and endothelial systems [34].…”

“…The BM of mutant mice exhibited a marked loss of CAR cells and a decreased proliferation in vitro [34]. Moreover, the BM of bis À/À mice exhibited markedly dilated sinusoids, a decrease in capillary density and the loss of endothelial cells in the BM, thus demonstrating the association between the mesenchymal (reticular) and endothelial systems [34]. However, in contrast to the vascular niche, the osteoblastic component of the bis À/À BM was not affected in the mutant mice.…”

“…In the case of mice with a disruption in Nf2/merlin, HSC frequencies were increased and shifted into the circulation, which was associated with an increase in trabecular bone mass and stromal cell numbers, as well as increased vascularity and VEGF levels [47]. On the contrary, molecules whose disruption can cause a defect in the vascular niche have been identified, as seen in the targeted disruption of bis [34]. Similarly, loss of the murine homologue of FANCB led to microenvironmental defects mimicking the hematological signs of fanconi anemia, which was rescued by the adoptive transfer of wild-type MSCs [48].…”