mTORC2/RICTOR exerts differential levels of metabolic control in human embryonic, mesenchymal and neural stem cells

Chu, Qun; Liu, Feifei; He, Yifang; Jiang, Xiaoyu; Cai, Yusheng; Wu, Zeming; Ke, Yan; Geng, Li; Zhang, Yichen; Feng, Huiyu; Zhou, Kaixin; Wang, Si; Zhang, Weiqi; Liu, Guang‐Hui; Ma, Shuai; Qu, Jing; Song, Moshi

doi:10.1007/s13238-021-00898-9

Cited by 10 publications

(5 citation statements)

References 15 publications

(18 reference statements)

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“…However, mTORC2-deficiency in hESCs reduces cellular interaction and impairs the mesendoderm differentiation. Although our findings agree with a recent report that RICTOR -knockout H9 hESCs hinders mesoderm differentiation, the RIC-KO H9 hESCs have a reduced ability of self-renewal 38 . This discrepancy is unlikely due to different genetic backgrounds as both H1 and H7 hESC lines in our studies revealed similar phenotypes after eliminating mTORC2.…”

Section: Discussionsupporting

confidence: 92%

mTORC2-mediated cell-cell interaction promote BMP4-induced WNT activation and mesoderm differentiation

Tong,

Batool,

Chiu

et al. 2024

Preprint

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The mechanistic target of rapamycin complex 2 (mTORC2) is essential for embryonic development but the underlying molecular mechanisms remain unclear. Here we show that disruption of mTORC2 in human embryonic stem cells (hESCs) considerably alters the balance of Rho/Rac signaling and reduces cell adhesion. Although these changes have no clear effect on hESC self-renewal and the expression of pluripotent markers, they significantly avert BMP-induced activation of canonical WNT genes, leading to impaired mesendoderm differentiation. Direct activation of downstream WNT pathway by inhibiting GSK3 dramatically improves mesendoderm differentiation in mTORC2-deficient hESCs. Our study uncovers a new mechanism by which mTORC2 regulates cell fate determination and, more importantly, link the intercellular contacts with the activation of the WNT genes.

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Section: Discussionsupporting

confidence: 92%

mTORC2-mediated cell-cell interaction promote BMP4-induced WNT activation and mesoderm differentiation

Tong,

Batool,

Chiu

et al. 2024

Preprint

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“…The role of mitochondrial respiration was assessed via the addition of different regulators, and the OCR was analyzed according to previous studies with some modifications [ 15 , 16 ]. Two days before the experiment, hMSCs were seeded at a density of 1.4 × 10 4 cells per Seahorse culture microplate well on gelatin-coated plates.…”

Section: Methodsmentioning

confidence: 99%

MAVS Antagonizes Human Stem Cell Senescence as a Mitochondrial Stabilizer

et al. 2023

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Mitochondrial dysfunction is a hallmark feature of cellular senescence and organ aging. Here, we asked whether the mitochondrial antiviral signaling protein (MAVS), which is essential for driving antiviral response, also regulates human stem cell senescence. To answer this question, we used CRISPR/Cas9-mediated gene editing and directed differentiation techniques to generate various MAVS-knockout human stem cell models. We found that human mesenchymal stem cells (hMSCs) were sensitive to MAVS deficiency, as manifested by accelerated senescence phenotypes. We uncovered that the role of MAVS in maintaining mitochondrial structural integrity and functional homeostasis depends on its interaction with the guanosine triphosphatase optic atrophy type 1 (OPA1). Depletion of MAVS or OPA1 led to the dysfunction of mitochondria and cellular senescence, whereas replenishment of MAVS or OPA1 in MAVS-knockout hMSCs alleviated mitochondrial defects and premature senescence phenotypes. Taken together, our data underscore an uncanonical role of MAVS in safeguarding mitochondrial homeostasis and antagonizing human stem cell senescence.

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“…The hMSCs were generated from hESCs. Briefly, embryoid bodies derived from hESCs were seeded on 6-well plates coated with Matrigel (BD Biosciences, 354230), the cells were cultured for about 14 days in hMSCs differentiation medium, which was performed as previously reported ( Liang et al, 2021; Chu et al, 2022 ). The differentiation medium was changed every other day until the fibroblast-like cells appeared and reached confluent.…”

Section: Methodsmentioning

confidence: 99%

Identification of FOXO1 as a geroprotector in human synovium through single-nucleus transcriptomic profiling

Liu,

Lu,

Wang

et al. 2023

Protein &Amp; Cell

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The synovium, a thin layer of tissue that adjacent to the joints and secretes synovial fluid, undergoes changes in aging that contribute to intense shoulder pain and other joint diseases. However, the mechanism underlying human synovial aging remains poorly characterized. Here, we generated a comprehensive profile of synovial cell types present in subacromial synovium from young and aged individuals. By delineating aging-related transcriptomic changes across cell types and their associated regulatory networks, we identified two subsets of mesenchymal stromal cell (MSC) in human synovium, which are lining and sublining MSCs, and found that angiogenesis and fibrosis-associated genes were upregulated whereas genes associated with cell adhesion and cartilage development were downregulated during aging. Moreover, the specific cell-cell communications in aged synovium mirrors that of aging-related inflammation and tissue remodeling, including vascular hyperplasia and tissue fibrosis. In particular, we identified Forkhead box O1 (FOXO1) as one of the major regulons for aging DEGs of synovium MSCs, and validated its downregulation in both lining and sublining MSC populations of the aged synovium. In human FOXO1-depleted MSCs derived from human embryonic stem cells, we recapitulated the senescent phenotype observed in the subacromial synovium of aged donors. These data indicate the important role for FOXO1 in the regulation of human synovial aging. Overall, our study improves upon our understanding of synovial aging during joint degeneration, thereby informing development of new treatments aimed at rejuvenating the aged joint.

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mTORC2/RICTOR exerts differential levels of metabolic control in human embryonic, mesenchymal and neural stem cells

Cited by 10 publications

References 15 publications

mTORC2-mediated cell-cell interaction promote BMP4-induced WNT activation and mesoderm differentiation

mTORC2-mediated cell-cell interaction promote BMP4-induced WNT activation and mesoderm differentiation

MAVS Antagonizes Human Stem Cell Senescence as a Mitochondrial Stabilizer

Identification of FOXO1 as a geroprotector in human synovium through single-nucleus transcriptomic profiling

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