Osteopontin promotes the development of natural killer cells from hematopoietic stem cells.
The detailed mechanisms driving the development of natural killer (NK) cells from hematopoietic stem cells remain to be clearly elucidated. Here, we show that osteopontin (OPN) is a key factor for NK development. OPN-deficient mice evidenced severe impairments of NK development in bone marrow (BM) and spleen in which the NK populations that express CD122 and NK cell receptors were reduced. However, the absence of intrinsic OPN expression did not affect NK development, whereas the absence of OPN in the microenvironment caused a significant reduction in NK population. The expression of OPN was induced by interleukin (IL)-15 in BM stromal cells, and the defect in NK differentiation in IL-15(-/-) hematopoietic precursor cells (HPC) was recovered by addition of recombinant OPN, suggesting that the microenvironmental OPN may be a key factor in IL-15-mediated NK differentiation. In addition, OPN-driven NK maturation was reduced in T-bet-deficient HPC, suggesting that T-bet is required for OPN-mediated NK development. Collectively, these results show that paracrine OPN signaling drives NK-lineage commitment, thus ultimately promoting NK cell development. Disclosure of potential conflicts of interest is found at the end of this article.
Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong, Taejon 305-333, Republic of Korea.
Jin Woong
JW
Chung
Mi Sun
MS
Kim
Zheng-Hao
ZH
Piao
Mira
M
Jeong
Suk Ran
SR
Yoon
Nara
N
Shin
Sang Yong
SY
Kim
Eun Sook
ES
Hwang
Young
Y
Yang
Young Ho
YH
Lee
Young Sang
YS
Kim
Inpyo
I
Choi
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D019409:Interleukin-15 / Q000096:biosynthesis* / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D053495:Osteopontin / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry; D013154:Spleen / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism*; D000098815:T-bet Transcription Factor
D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; D011994:Recombinant Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D053495:Osteopontin