mTOR Signaling as a Regulator of Hematopoietic Stem Cell Fate

Fernandes, Hélia; Moura, José; Carvalho, Eugénia

doi:10.1007/s12015-021-10131-z

Cited by 22 publications

(23 citation statements)

References 158 publications

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“…Interestingly, upon sequencing analysis of Myh9 -deficient LSK cells, we found that one prosurvival signaling gene set critical for mTOR function was markedly downregulated, while the other one that is important for intrinsic apoptotic signaling pathway by p53 was markedly upregulated ( Figure 6 ). Since the loss of mTOR in hematopoiesis was sufficient to cause pancytopenia and impairment of HSC homeostasis [ 38 ] and P53 pathway was activated by DNA damage and played an important role in regulating HSC quiescence, self-renewal, and apoptosis, our results indicated that defects observed in Myh9 -deficient mice might cause a perturbation of multiple genes and signaling pathways related to HSC maintenance. Recent reports have shown that Myh9 is crucial for maintaining stemness of lung cancer cells and promoting tumorigenesis via activating mTOR signals [ 39 , 40 ], suggesting Myh9 may exert a profound function on stem cells.…”

Section: Discussionmentioning

confidence: 89%

Myh9 Plays an Essential Role in the Survival and Maintenance of Hematopoietic Stem/Progenitor Cells

Dong

Cao

et al. 2022

Cells

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Myosin heavy chain 9 (MYH9) gene encodes a protein named non-muscle heavy chain IIA (NMHC IIA), interacting with actin and participating in various biological processes. Mutations in MYH9 cause an array of autosomal dominant disorders, known as MYH9-related diseases (MYH9-RD). However, the role of MYH9 in normal hematopoiesis remains largely unexplored. By using Mx1-cre Myh9 conditional knockout mice, we established an inducible system to precisely inactivate Myh9 function in hematopoietic cells in vivo. The results showed that deletion of Myh9 led to severe defects in hematopoiesis, characterized by pancytopenia, drastic decreases of hematopoietic stem/progenitor cells (HSPC), and bone marrow failure, causing early lethality in mice. The defect in hematopoiesis caused by Myh9 ablation is cell autonomous. In addition, Myh9 deletion impairs HSPC repopulation capacity and increases apoptosis. RNA sequencing results revealed significant alterations in the expression of genes related to HSC self-renewal and maintenance, while multiple signal pathways were also involved, including genes for HSC and myeloid cell development, intrinsic apoptosis, targets of mTOR signaling, and maturity of hematopoietic cells. Our present study suggests an essential role for Myh9 in the survival and maintenance of HSPC in normal hematopoiesis.

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Section: Discussionmentioning

confidence: 89%

Myh9 Plays an Essential Role in the Survival and Maintenance of Hematopoietic Stem/Progenitor Cells

Dong

Cao

et al. 2022

Cells

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“…In this regard, GSKIP is an anchoring protein for GSK3β and PKA, which are involved in the regulation of multiple cellular signaling pathways, including the Wnt/β-catenin and PI3K/AKT/mTOR pathways ( 23 – 26 ). Accumulating evidence suggests that the Wnt/β-catenin and mTOR pathways play an important role in determining the fate of normal HSCs, including quiescence, self-renewal, and differentiation statuses ( 48 , 49 ), and also help determine the nature of MPN stem cells ( 3 – 6 ). We speculate that although mice with loss of Gskip alone showed no particular phenotype in the hematopoietic system, probably due to functional redundancy in the signaling network in mice, deficiency of Gskip with concomitant ablation of Atg2b may be over the redundancy threshold.…”

Section: Discussionmentioning

confidence: 99%

Loss of Atg2b and Gskip Impairs the Maintenance of the Hematopoietic Stem Cell Pool Size

Sakai

Hasegawa

Ishimura

et al. 2022

Molecular and Cellular Biology

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A germline copy number duplication of chromosome 14q32, which contains ATG2B and GSKIP , was identified in families with myeloproliferative neoplasm (MPN). Herein, we show that mice lacking both Atg2b and Gskip , but not either alone, exhibited decreased hematopoiesis, resulting in death in utero accompanied by anemia. In marked contrast to MPN patients with duplication of ATG2B and GSKIP , the number of hematopoietic stem cells (HSCs), in particular long-term HSCs, in double knockout fetal livers were significantly decreased due to increased cell death. Although the remaining HSCs still had the ability to differentiate into hematopoietic progenitor cells, the differentiation efficiency was quite low. Remarkably, mice with knockout of Atg2b or Gskip alone did not show any hematopoietic abnormality. Mechanistically, while loss of both genes had no effect on autophagy, it increased the expression of genes encoding enzymes involved in oxidative phosphorylation. Taken together, our results indicate that Atg2b and Gskip play a synergistic effect in maintaining the pool size of HSCs.

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Section: Discussionmentioning

confidence: 99%

“…mTOR is a master regulator of hematopoiesis 17 , 19 , 20 . IPA of our multi-omics analysis indicates that 14 days in vitro culture led to an activation of RICTOR, RAPTOR and mTORC1, but inactivation of TSC2-mediated molecular pathways, the latter most likely via AKT 19 , 32 , 33 , 51 . This indicated a general activation of mTOR, particularly mTORC1 in parallel to ongoing differentiation of HSCs in culture during their expansion, which is in line with the literature 17 , 19 , 20 .…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of hematopoietic stem cells after in vitro amplification on biomimetic 3D PDMS cell culture scaffolds

Marx-Blümel

Marx

Sonnemann

et al. 2021

Sci Rep

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Hematopoietic stem cell (HSC) transplantation is successfully applied since the late 1950s. However, its efficacy can be impaired by insufficient numbers of donor HSCs. A promising strategy to overcome this hurdle is the use of an advanced ex vivo culture system that supports the proliferation and, at the same time, maintains the pluripotency of HSCs. Therefore, we have developed artificial 3D bone marrow-like scaffolds made of polydimethylsiloxane (PDMS) that model the natural HSC niche in vitro. These 3D PDMS scaffolds in combination with an optimized HSC culture medium allow the amplification of high numbers of undifferentiated HSCs. After 14 days in vitro cell culture, we performed transcriptome and proteome analysis. Ingenuity pathway analysis indicated that the 3D PDMS cell culture scaffolds altered PI3K/AKT/mTOR pathways and activated SREBP, HIF1α and FOXO signaling, leading to metabolic adaptations, as judged by ELISA, Western blot and metabolic flux analysis. These molecular signaling pathways can promote the expansion of HSCs and are involved in the maintenance of their pluripotency. Thus, we have shown that the 3D PDMS scaffolds activate key molecular signaling pathways to amplify the numbers of undifferentiated HSCs ex vivo effectively.

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mTOR Signaling as a Regulator of Hematopoietic Stem Cell Fate

Cited by 22 publications

References 158 publications

Myh9 Plays an Essential Role in the Survival and Maintenance of Hematopoietic Stem/Progenitor Cells

Myh9 Plays an Essential Role in the Survival and Maintenance of Hematopoietic Stem/Progenitor Cells

Loss of Atg2b and Gskip Impairs the Maintenance of the Hematopoietic Stem Cell Pool Size

Molecular characterization of hematopoietic stem cells after in vitro amplification on biomimetic 3D PDMS cell culture scaffolds

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