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P18 的过表达对造血不同阶段的独特影响涉及 TGF-β 和 NF-κB 信号通路。

The distinct effects of P18 overexpression on different stages of hematopoiesis involve TGF-β and NF-κB signaling.

机构信息

Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Chengdu, 610052, China.

State Key Laboratory of Experimental Hematology, CAMS & PUMC, Tianjin, 300020, China.

出版信息

Sci Rep. 2021 Dec 14;11(1):24014. doi: 10.1038/s41598-021-03263-2.

DOI:10.1038/s41598-021-03263-2
PMID:34907231
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8671498/
Abstract

Deficiency of P18 can significantly improve the self-renewal potential of hematopoietic stem cells (HSC) and the success of long-term engraftment. However, the effects of P18 overexpression, which is involved in the inhibitory effects of RUNX1b at the early stage of hematopoiesis, have not been examined in detail. In this study, we established inducible P18/hESC lines and monitored the effects of P18 overexpression on hematopoietic differentiation. Induction of P18 from day 0 (D0) dramatically decreased production of CD34CD43- cells and derivative populations, but not that of CD34CD43- cells, changed the cell cycle status and apoptosis of KDR+ cells and downregulated the key hematopoietic genes at D4, which might cause the severe blockage of hematopoietic differentiation at the early stage. By contrast, induction of P18 from D10 dramatically increased production of classic hematopoietic populations and changed the cell cycle status and apoptosis of CD45+ cells at D14. These effects can be counteracted by inhibition of TGF-β or NF-κB signaling respectively. This is the first evidence that P18 promotes hematopoiesis, a rare property among cyclin-dependent kinase inhibitors (CKIs).

摘要

P18 缺乏可显著提高造血干细胞 (HSC) 的自我更新能力和长期植入的成功率。然而，参与造血早期 RUNX1b 抑制作用的 P18 过表达的影响尚未详细研究。在这项研究中，我们建立了可诱导的 P18/hESC 系，并监测了 P18 过表达对造血分化的影响。从第 0 天 (D0) 诱导 P18 可显著降低 CD34CD43-细胞及其衍生群体的产生，但不改变 CD34CD43-细胞的产生，改变 KDR+细胞的细胞周期状态和凋亡，并在第 4 天下调关键造血基因，这可能导致早期造血分化严重受阻。相比之下，从第 10 天 (D10) 诱导 P18 可显著增加经典造血群体的产生，并改变第 14 天 CD45+细胞的细胞周期状态和凋亡。这些作用可以分别通过抑制 TGF-β 或 NF-κB 信号通路来拮抗。这是 P18 促进造血的第一个证据，在细胞周期蛋白依赖性激酶抑制剂 (CKIs) 中很少见。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21c9/8671498/608b37538d32/41598_2021_3263_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21c9/8671498/5f8a2c164906/41598_2021_3263_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21c9/8671498/608b37538d32/41598_2021_3263_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21c9/8671498/4b5f839e23e0/41598_2021_3263_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21c9/8671498/858d352effbb/41598_2021_3263_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21c9/8671498/6203004374ec/41598_2021_3263_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21c9/8671498/ab023bfc120e/41598_2021_3263_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21c9/8671498/36bded715a10/41598_2021_3263_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21c9/8671498/49f945770aa1/41598_2021_3263_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21c9/8671498/5f8a2c164906/41598_2021_3263_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21c9/8671498/608b37538d32/41598_2021_3263_Fig8_HTML.jpg

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本文引用的文献

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Overexpression of HOXA9 upregulates NF-κB signaling to promote human hematopoiesis and alter the hematopoietic differentiation potentials.HOXA9的过表达上调NF-κB信号传导，以促进人类造血并改变造血分化潜能。
Cell Regen. 2021 Jan 11;10(1):9. doi: 10.1186/s13619-020-00066-0.
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