Srebf1c preserves hematopoietic stem cell function and survival as a switch of mitochondrial metabolism

Lu, Yukai; Zhang, Zihao; Wang, Song; Qi, Yan; Chen, Fang; Xu, Yu; Shen, Mingqiang; Chen, Mo; Chen, Naicheng; Yang, Lijing; Chen, Shilei; Wang, Fengchao; Su, Yongping; Hu, Mengjia; Wang, Junping

doi:10.1016/j.stemcr.2022.01.011

Cited by 7 publications

(9 citation statements)

References 55 publications

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“…This patient displayed a high frequency of monocyte/dendritic cell progenitors with strong inflammatory profile but also the upregulation of several stress-induced factors (such as JUND or SREBF1 ) in HSCs, which might have been responsible for the functional defects. 46 , 47 This situation was reminiscent of HSC exhaustion through chronic IFN pathway activation. 39 Based on the strong activation of the Jun/Fos pathway, we cannot exclude the synergic contribution of additional inflammatory pathways participating in HSC exhaustion, such as the TLR4/TRIF pathway.…”

Section: Discussionmentioning

confidence: 99%

Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy

Sobrino¹,

Magnani²,

Semeraro³

et al. 2023

Cell Reports Medicine

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Section: Discussionmentioning

confidence: 99%

Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy

Sobrino¹,

Magnani²,

Semeraro³

et al. 2023

Cell Reports Medicine

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“…Peripheral blood (PB) was obtained from the tail vein of mice and then diluted in 1% EDTA solution. The counts of white blood cell (WBC), red blood cell (RBC) and platelet (PLT) were analyzed automatically on the XT-1800i/2000IV hematology analyzer (Sysmex, Kobe, Japan) as we described 19 .…”

Section: Methodsmentioning

confidence: 99%

Melanocortin/MC5R axis regulates the proliferation of hematopoietic stem cells in mice after ionizing radiation injury

et al. 2023

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Hematopoietic stem cells (HSCs) possess the great self-renewal and multidirectional differentiation ability, which contributes to the continuous generation of various blood cells. Although many intrinsic and extrinsic factors have been found to maintain HSC homeostasis, how to precisely regulate hematopoiesis under stress conditions is poorly understood. In this study, we show that melanocortin receptor 5 (MC5R) is abundantly expressed in hematopoietic stem progenitor cells (HSPCs). Using a MC5R knockout (MC5R-/-) mouse model, we observe that it is not essential for steady-state hematopoiesis. Interestingly, the levels of α-melanocyte stimulating hormone (α-MSH), an important sub-type of melanocortin, are elevated in serum and bone marrow, and the expression of MC5R is upregulated in HSPCs from mice after irradiation. MC5R deficiency aggravates irradiation-induced myelosuppression due to the impairment in the proliferation and reconstitution function of HSCs. Further investigations exhibit that melanocortin/MC5R axis regulates the proliferation of HSCs through activating the PI3K/AKT and MAPK pathways. More importantly, α-MSH treatment can significantly accelerate the hematopoietic recovery in irradiated mice. In conclusion, our data demonstrate that melanocortin/MC5R axis plays a crucial role in regulating HSC proliferation under stress, thus providing a promising strategy to promote hematopoietic regeneration when suffering from injury.

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“…Mouse BM and PB samples were prepared as we described [ 8 , 24 ]. To analyze the phenotype of normal hematopoietic cells, samples were stained with anti-lineage cocktail (anti-CD3e, anti-CD11b, anti-Gr-1, anti-B220 and anti-Ter-119), anti-Sca-1, anti-c-Kit, anti-CD34, anti-Flk2, anti-CD150, anti-CD48, anti-CD127, anti-CD16/32, anti-Gr-1, anti-CD11b, anti-B220, anti-CD3e, anti-CD45.1 and anti-CD45.2.…”

Section: Methodsmentioning

confidence: 99%

“…To analyze the phenotype of LSCs, anti-lineage cocktail, anti-Sca-1, anti-c-Kit, anti-CD34 and anti-CD16/32 were used. The apoptosis, cell cycle, in vivo BrdU incorporation and intracellular staining assays were performed following our previous protocols [ 24 ]. Flow cytometry analysis was conducted using a FACSVerse (BD Biosciences, San Jose, CA, USA) or ID7000 (Sony Biotechnology, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…For cell sorting, a Direct Lineage Cell Depletion Kit (Miltenyi Biotec, Bergisch Gladbach, Germany) was used to delete the mature cells and then samples were stained with above antibodies, followed by sorting using a FACSAria III (BD Biosciences). Gating strategies are referred to our previous studies [ 8 , 24 ]. The details of antibodies are provided in Supplementary Table S1 .…”

Section: Methodsmentioning

confidence: 99%

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Tespa1 facilitates hematopoietic and leukemic stem cell maintenance by restricting c-Myc degradation

Yang

Shen

et al. 2023

Leukemia

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Hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) have robust self-renewal potential, which is responsible for sustaining normal and malignant hematopoiesis, respectively. Although considerable efforts have been made to explore the regulation of HSC and LSC maintenance, the underlying molecular mechanism remains obscure. Here, we observe that the expression of thymocyte-expressed, positive selection-associated 1 (Tespa1) is markedly increased in HSCs after stresses exposure. Of note, deletion of Tespa1 results in short-term expansion but long-term exhaustion of HSCs in mice under stress conditions due to impaired quiescence. Mechanistically, Tespa1 can interact with CSN subunit 6 (CSN6), a subunit of COP9 signalosome, to prevent ubiquitination-mediated degradation of c-Myc protein in HSCs. As a consequence, forcing c-Myc expression improves the functional defect of Tespa1-null HSCs. On the other hand, Tespa1 is identified to be highly enriched in human acute myeloid leukemia (AML) cells and is essential for AML cell growth. Furthermore, using MLL-AF9-induced AML model, we find that Tespa1 deficiency suppresses leukemogenesis and LSC maintenance. In summary, our findings reveal the important role of Tespa1 in promoting HSC and LSC maintenance and therefore provide new insights on the feasibility of hematopoietic regeneration and AML treatment.

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Srebf1c preserves hematopoietic stem cell function and survival as a switch of mitochondrial metabolism

Cited by 7 publications

References 55 publications

Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy

Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy

Melanocortin/MC5R axis regulates the proliferation of hematopoietic stem cells in mice after ionizing radiation injury

Tespa1 facilitates hematopoietic and leukemic stem cell maintenance by restricting c-Myc degradation

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