Knockdown of N-cadherin suppresses the long-term engraftment of hematopoietic stem cells.
During postnatal life, the bone marrow (BM) supports both self-renewal and differentiation of hematopoietic stem cells (HSCs) in specialized microenvironments termed stem cell niches. Cell-cell and cell-extracellular matrix interactions between HSCs and their niches are critical for the maintenance of HSC properties. Here, we analyzed the function of N-cadherin in the regulation of the proliferation and long-term repopulation activity of hematopoietic stem/progenitor cells (HSPCs) by the transduction of N-cadherin shRNA. Inhibition of N-cadherin expression accelerated cell division in vitro and reduced the lodgment of donor HSPCs to the endosteal surface, resulting in a significant reduction in long-term engraftment. Cotransduction of N-cadherin shRNA and a mutant N-cadherin that introduced the silent mutations to shRNA target sequences rescued the accelerated cell division and reconstitution phenotypes. In addition, the requirement of N-cadherin for HSPC engraftment appears to be niche specific, as shN-cad-transduced lineage(-)Sca-1(+)c-Kit(+) cells successfully engrafted in spleen, which lacks an osteoblastic niche. These findings suggest that N-cad-mediated cell adhesion is functionally required for the establishment of hematopoiesis in the BM niche after BM transplantation.
Hosokawa
Kentaro
K
Department of Cell Differentiation, Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, Japan.
Arai
Fumio
F
Yoshihara
Hiroki
H
Iwasaki
Hiroko
H
Nakamura
Yuka
Y
Gomei
Yumiko
Y
Suda
Toshio
T
D000818:Animals; D015820:Cadherins / Q000235:genetics* / Q000502:physiology; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D006085:Graft Survival / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D055153:Stem Cell Niche / Q000502:physiology; D013997:Time Factors
D015820:Cadherins