The endoplasmic reticulum chaperone protein GRP94 is required for maintaining hematopoietic stem cell interactions with the adult bone marrow niche.
The endoplasmic reticulum chaperone protein GRP94 is required for maintaining hematopoietic stem cell interactions with the adult bone marrow niche.
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DOI：
10.1371/journal.pone.0020364
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Lee AS
中科院分区：
文献类型：
--
作者：
Luo B;Lam BS;Lee SH;Wey S;Zhou H;Wang M;Chen SY;Adams GB;Lee AS
成人骨髓中的造血干细胞（HSC）稳态是由内在基因表达产物和HSC生态位中与外部因素的相互作用共同调控的。GRP94是一种内质网伴侣，据报道，GRP94对特异性整合素的表达和选择性地调节早期T和B淋巴生成至关重要。在GRP94缺失的骨髓嵌合体中，多能造血祖细胞持续存在，甚至增加，但其机制尚不清楚。在这里，我们采用条件敲除（KO）策略来急性消除造血系统中的GRP94。我们观察到Grp94 KO BM中造血干细胞和粒细胞单核细胞祖细胞的增加，这与集落形成单位数量的增加有关。细胞周期分析显示，静止的丧失和增殖的增加导致Grp94 KO hsc的增加。造血干细胞池的扩大可归因于造血干细胞与生态位的相互作用受损，这可以通过造血干细胞动员增强和原始造血细胞归巢和倒立能力严重受损来证明。将野生型（WT）造血细胞移植到没有GRP94的微环境中，与WT对照相比，产生了正常的血液学特征和相当数量的HSC，这表明HSC中的GRP94是维持HSC稳态所必需的，而不是小生境细胞。为此，我们进一步确定Grp94 KO hsc细胞表面的整合素α4表达几乎完全缺失，这表明与纤维连接蛋白的结合受损，纤维连接蛋白是一种已知在介导hsc -生态位相互作用中起作用的细胞外基质分子。此外，Grp94 KO小鼠表现出骨髓和淋巴细胞分化的改变。总之，我们的研究证实GRP94是维持造血干细胞与其生态位相互作用所需的一种新的细胞内在因子，从而调节其生理。
Hematopoietic stem cell (HSC) homeostasis in the adult bone marrow (BM) is regulated by both intrinsic gene expression products and interactions with extrinsic factors in the HSC niche. GRP94, an endoplasmic reticulum chaperone, has been reported to be essential for the expression of specific integrins and to selectively regulate early T and B lymphopoiesis. In GRP94 deficient BM chimeras, multipotent hematopoietic progenitors persisted and even increased, however, the mechanism is not well understood. Here we employed a conditional knockout (KO) strategy to acutely eliminate GRP94 in the hematopoietic system. We observed an increase in HSCs and granulocyte-monocyte progenitors in the Grp94 KO BM, correlating with an increased number of colony forming units. Cell cycle analysis revealed that a loss of quiescence and an increase in proliferation led to an increase in Grp94 KO HSCs. This expansion of the HSC pool can be attributed to the impaired interaction of HSCs with the niche, evidenced by enhanced HSC mobilization and severely compromised homing and lodging ability of primitive hematopoietic cells. Transplanting wild-type (WT) hematopoietic cells into a GRP94 null microenvironment yielded a normal hematology profile and comparable numbers of HSCs as compared to WT control, suggesting that GRP94 in HSCs, but not niche cells, is required for maintaining HSC homeostasis. Investigating this, we further determined that there was a near complete loss of integrin α4 expression on the cell surface of Grp94 KO HSCs, which showed impaired binding with fibronectin, an extracellular matrix molecule known to play a role in mediating HSC-niche interactions. Furthermore, the Grp94 KO mice displayed altered myeloid and lymphoid differentiation. Collectively, our studies establish GRP94 as a novel cell intrinsic factor required to maintain the interaction of HSCs with their niche, and thus regulate their physiology.
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DOI：
10.4049/jimmunol.1000448
发表时间：
2010-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Jockheck-Clark AR;Bowers EV;Totonchy MB;Neubauer J;Pizzo SV;Nicchitta CV
通讯作者：
Nicchitta CV
影响因子：
5.2
作者：
Lymperi S;Ferraro F;Scadden DT
通讯作者：
Scadden DT
DOI：
10.1196/annals.1402.086
发表时间：
2007-01-01
期刊：
SKELETAL BIOLOGY AND MEDICINE, PT A
影响因子：
--
作者：
Mendez-Ferrer, Simon;Frenette, Paul S.
通讯作者：
Frenette, Paul S.
影响因子：
64.8
作者：
Hock, H;Hamblen, MJ;Orkin, SH
通讯作者：
Orkin, SH
DOI：
10.1073/pnas.0807691105
发表时间：
2008-12-09
影响因子：
11.1
作者：
Fu, Yong;Wey, Shiuan;Lee, Amy S.
通讯作者：
Lee, Amy S.