Disruption of bis leads to the deterioration of the vascular niche for hematopoietic stem cells.
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.
Kwon
Kyung-Rim
KR
Catholic Cell Therapy Center & Department of Cellular Medicine, The Catholic University of Korea, Seoul, Korea.
Ahn
Ji-Yeon
JY
Kim
Myung-Shin
MS
Jung
Joo-Young
JY
Lee
Jeong-Hwa
JH
Oh
Il-Hoan
IH
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D007150:Immunohistochemistry; D015851:Interleukin-7 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D054377:Chemokine CXCL12; D015851:Interleukin-7