Nat Med:巨核細胞可控制造血幹細胞 有望治療多種疾病

2014年10月21日 訊 /生物谷BIOON/ --巨核細胞被認為是產生血小板癒合傷口最好的細胞，這些在骨髓中發現的巨大細胞在調節幹細胞上也扮演著重要的角色，這是近日來自美國密蘇裡州斯託瓦斯醫學研究所（Stowers Institute for Medical Research）的研究人員的一項重大研究發現，相關研究成果刊登於國際雜誌Nature Medicine上。

實際上，造血幹細胞在骨髓中可以分化形成巨核細胞，而本文研究者也首次發現造血幹細胞可以直接被巨核細胞所控制，即母體細胞會被子代細胞所控制；研究者Meng Zhao博士表示，我們的研究結果顯示，巨核細胞或許可以被應用於臨床中來促進成體幹細胞進行細胞再生，並且擴大細胞的培養來用於進行成體幹細胞的移植。巨核細胞可以直接調節鼠類造血幹細胞的功能，而成體幹細胞可以形成血液和免疫細胞用以更新機體的血液供應，這些成體幹細胞也可以分化產生多種類型的血細胞，包括白細胞、紅細胞及血小板等。

由於具有自我更新及分化形成多種類型細胞的能力，因此近年來造血幹細胞受到了科學界的極大關注，研究者已經開始利用造血幹細胞進行許多人類疾病的治療；而離體的人類造血幹細胞的移植也用於治療貧血、免疫缺陷及其它疾病。研究人員表示，巨核細胞可以通過「告知」造血幹細胞何時應該休眠，何時應該增殖滿足機體需求來直接調節造血幹細胞的水平；而維持造血幹細胞產量的平衡也至關重要。

最後研究者Li說道，我們的研究揭示了，巨核細胞是患者化療後機體造血幹細胞恢復功能所必需的，本文研究為利用巨核細胞衍生的因子，比如TGF-B1和FGF1來促進造血幹細胞再生提供了新的思路和幫助，後期研究者將通過研究分析是否巨核細胞的生境可以用於幫助造血幹細胞在體外進行擴大培養和移植。（生物谷Bioon.com）

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Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells

Meng Zhao, John M Perry, Heather Marshall, Aparna Venkatraman, Pengxu Qian, Xi C He, Jasimuddin Ahamed & Linheng Li

Multiple bone marrow stromal cell types have been identified as hematopoietic stem cell (HSC)-regulating niche cells1, 2, 3, 4, 5, 6, 7. However, whether HSC progeny can serve directly as HSC niche cells has not previously been shown. Here we report a dichotomous role of megakaryocytes (MKs) in both maintaining HSC quiescence during homeostasis and promoting HSC regeneration after chemotherapeutic stress. We show that MKs are physically associated with HSCs in the bone marrow of mice and that MK ablation led to activation of quiescent HSCs and increased HSC proliferation. RNA sequencing (RNA-seq) analysis revealed that transforming growth factor β1 (encoded by Tgfb1) is expressed at higher levels in MKs as compared to other stromal niche cells. MK ablation led to reduced levels of biologically active TGF-β1 protein in the bone marrow and nuclear-localized phosphorylated SMAD2/3 (pSMAD2/3) in HSCs, suggesting that MKs maintain HSC quiescence through TGF-β–SMAD signaling8, 9. Indeed, TGF-β1 injection into mice in which MKs had been ablated restored HSC quiescence, and conditional deletion of Tgfb1 in MKs increased HSC activation and proliferation. These data demonstrate that TGF-β1 is a dominant signal emanating from MKs that maintains HSC quiescence. However, under conditions of chemotherapeutic challenge, MK ablation resulted in a severe defect in HSC expansion. In response to stress, fibroblast growth factor 1 (FGF1) signaling from MKs transiently dominates over TGF-β inhibitory signaling to stimulate HSC expansion10, 11. Overall, these observations demonstrate that MKs serve as HSC-derived niche cells to dynamically regulate HSC function.