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Haematologica 2021 Volume 106(2):412-423
Hematopoiesis
MicroRNA-21 maintains hematopoietic stem cell homeostasis through sustaining the nuclear factor-κB signaling pathway in mice
Mengjia Hu, Yukai Lu, Hao Zeng, Zihao Zhang, Shilei Chen, Yan Qi, Yang Xu, Fang Chen, Yong Tang, Mo Chen, Changhong Du, Mingqiang Shen, Fengchao Wang, Yongping Su, Song Wang# and Junping Wang#
1State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
#SW and JW contributed equally as co-senior authors
ABSTRACT
Long-term hematopoietic output is dependent on hematopoietic stem cell (HSC) homeostasis which is maintained by a complex molecular network in which microRNA play crucial roles, although the underlying molecular basis has not been fully elucidated. Here we show that microRNA-21 (miR-21) is enriched in murine HSC, and that mice with conditional knockout of miR-21 exhibit an obvious perturba- tion in hematopoiesis. Moreover, significant loss of HSC quiescence and long-term reconstituting ability are observed in the absence of miR-21. Further studies revealed that miR-21 deficiency markedly decreases the nuclear factor kappa B (NF-κB) pathway, accompanied by increased expression of PDCD4, a direct target of miR-21, in HSC. Interestingly, overexpression of PDCD4 in wild-type HSC generates similar pheno- types as those of miR-21-deficient HSC. More importantly, knockdown of PDCD4 can significantly rescue the attenuation of NF-κB activity, thereby improving the defects in miR-21-null HSC. On the other hand, we found that miR-21 is capable of preventing HSC from ionizing radia- tion-induced DNA damage via activation of the NF-κB pathway. Collectively, our data demonstrate that miR-21 is involved in maintain- ing HSC homeostasis and function, at least in part, by regulating the PDCD4-mediated NF-κB pathway and provide a new insight into radio- protection of HSC.
Introduction
Hematopoiesis is a well-organized developmental process in which hematopoi- etic stem cells (HSC) can self-renew and differentiate into all kinds of blood cells.1,2 Under steady-state conditions, most adult HSC are retained in a relatively undiffer- entiated and quiescent state in the bone marrow (BM) microenvironment, which is necessary for sustaining long-term hematopoietic function.3,4 In contrast, the pertur- bation of HSC homeostasis may result in hematopoietic failure, immunodeficien- cies or hematologic malignancies.5,6 It was known that HSC homeostasis is tightly modulated by a complicated molecular network.7 In the past decades, many factors, including cell cycle proteins, transcription factors, surface receptors, epigenetic reg- ulatory factors, metabolic regulators, long non-coding RNA and cytokines, have been found to be involved in the control of HSC homeostasis.1,3,8,9 However, the underlying molecular mechanism is still not completely clear.
MicroRNA (miRNA) are small non-coding RNA that participate in a wide range of biological processes by negatively controlling the expression of their target genes through post-transcriptional regulation.10,11 Previous studies have shown that miRNA have distinct expression patterns in the hematopoietic system, and specific miRNA can affect the development of different blood-cell lineages.12,13 In recent years, several miRNA, such as miR-22, miR-29a, miR-125a, miR-126, and the miR- 132/122 cluster,7,14-17 have been shown to play important roles in HSC biology.
miR-21, a well-known short RNA, has multiple physiological functions in mam-
Correspondence:
JUNPING WANG
wangjunping@tmmu.edu.cn
Received: August 30, 2019. Accepted: January 20, 2020. Pre-published: January 23, 2020.
https://doi.org/10.3324/haematol.2019.236927
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