Rapamycin Rescues Age-Related Changes in Muscle-Derived Stem/Progenitor Cells from Progeroid Mice

Kawakami, Yoshiyuki; Hambright, William S.; Takayama, Koji; Mu, Xiaodong; Lü, Aiping; Cummins, James; Matsumoto, Tomoyuki; Yurube, Takashi; Kuroda, R.; Kurosaka, Masahiro; Fu, Freddie H.; Robbins, Paul D.; Niedernhofer, Laura J.; Huard, Johnny

doi:10.1016/j.omtm.2019.05.011

Cited by 39 publications

(33 citation statements)

References 82 publications

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“…In our study, cell proliferation was tested prior to sheet collection and at day 1 and 14, revealing that A-TSPC sheets have significantly lower cell density and proliferation rate than Y-TSPC sheets. Kawakami et al (2019) communicated that progeroid mice contained higher numbers of apoptotic muscle stem/progenitor cells. Taylor et al (2003) showed that in human colonic crypts, age-related DNA mutations are associated with stem cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Aged Tendon Stem/Progenitor Cells Are Less Competent to Form 3D Tendon Organoids Due to Cell Autonomous and Matrix Production Deficits

Zhi-yong

Yin

Brochhausen

et al. 2020

Front. Bioeng. Biotechnol.

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Tendons are dense connective tissues, which are critical for the integrity and function of our musculoskeletal system. During tendon aging and degeneration, tendon stem/progenitor cells (TSPCs) experience profound phenotypic changes with declined cellular functions that can be linked to the known increase in complications during tendon healing process in elderly patients. Tissue engineering is a promising approach for achieving a complete recovery of injured tendons. However, use of autologous cells from aged individuals would require restoring the cellular fitness prior to implantation. In this study, we applied an established cell sheet model for in vitro tenogenesis and compared the sheet formation of TSPC derived from young/healthy (Y-TSPCs) versus aged/degenerative (A-TSPCs) human Achilles tendon biopsies with the purpose to unravel differences in their potential to form self-assembled three-dimensional (3D) tendon organoids. Using our three-step protocol, 4 donors of Y-TSPCs and 9 donors of A-TSPCs were subjected to cell sheet formation and maturation in a period of 5 weeks. The sheets were then cross evaluated by weight and diameter measurements; quantification of cell density, proliferation, senescence and apoptosis; histomorphometry; gene expression of 48 target genes; and collagen type I protein production. The results revealed very obvious and significant phenotype in A-TSPC sheets characterized by being fragile and thin with poor tissue morphology, and significantly lower cell density and proliferation, but significantly higher levels of the senescence-related gene markers and apoptotic cells. Quantitative gene expression analyses at the mRNA and protein levels, also demonstrated abnormal molecular circuits in the A-TSPC sheets. Taken together, we report for the first time that A-TSPCs exhibit profound deficits in forming 3D tendon tissue organoids, thus making the cell sheet model suitable to investigate the molecular mechanisms involved in tendon aging and degeneration, as well as examining novel pharmacologic strategies for rejuvenation of aged cells.

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Section: Discussionmentioning

confidence: 99%

Aged Tendon Stem/Progenitor Cells Are Less Competent to Form 3D Tendon Organoids Due to Cell Autonomous and Matrix Production Deficits

Zhi-yong

Yin

Brochhausen

et al. 2020

Front. Bioeng. Biotechnol.

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“…In particular, MDSPCs isolated from prelamin A-expressing progeria mice exhibit increased mTOR signaling. This is accompanied by proliferation and differentiation deficiencies in culture and during tissue regeneration [49]. Inhibition of mTOR with rapamycin improved differentiation along myogenic and chondrogenic lineages and reduced the extent of apoptosis and senescence of MDSPCs.…”

Section: The Progeria Cell and Energymentioning

confidence: 99%

Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

Kreienkamp

Gonzalo

2020

Cells

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Hutchinson–Gilford Progeria Syndrome (HGPS) is a segmental premature aging disease causing patient death by early teenage years from cardiovascular dysfunction. Although HGPS does not totally recapitulate normal aging, it does harbor many similarities to the normal aging process, with patients also developing cardiovascular disease, alopecia, bone and joint abnormalities, and adipose changes. It is unsurprising, then, that as physicians and scientists have searched for treatments for HGPS, they have targeted many pathways known to be involved in normal aging, including inflammation, DNA damage, epigenetic changes, and stem cell exhaustion. Although less studied at a mechanistic level, severe metabolic problems are observed in HGPS patients. Interestingly, new research in animal models of HGPS has demonstrated impressive lifespan improvements secondary to metabolic interventions. As such, further understanding metabolism, its contribution to HGPS, and its therapeutic potential has far-reaching ramifications for this disease still lacking a robust treatment strategy.

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“…( 26 ) STE24 was already identified to process prelamin A to a mature nuclear form. ( 30 ) Mutation of Ste24 leads to premature‐aging disease, lipodystrophy, steatohepatitis, and skeletal abnormalities, ( 30,33,34 ) which are often seen in patients with AIDS under anti‐HIV therapies. For RCE1, our results support its association with Rab13 or Rab18, as levels of the two Rab proteins were reduced in the mouse liver treated with the anti‐HIV drugs.…”

Section: Discussionmentioning

confidence: 99%

Ritonavir and Lopinavir Suppress RCE1 and CAAX Rab Proteins Sensitizing the Liver to Organelle Stress and Injury

Khalatbari¹,

Mishra²,

Han³

et al. 2020

Hepatol Commun

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Organelle stress and Liver injuries often occur in human immunodeficiency virus (HIV) infected patients underanti-HIV therapies, yet few molecular off-targets of anti-HIV drugs have been identified in the liver. Here, we found through total RNA sequencing that the transcription of a host protease Ras converting CAAX endopeptidase 1 (RCE1) was altered in HepG2 cells treated with anti-HIV protease inhibitors, ritonavir and lopinavir. Levels of RCE1 protein were inhibited in HepG2 and primary mouse hepatocytes and in the liver of mice treated with the anti-HIV drugs, which were accompanied with inhibition of two potential substrates of RCE1, small GTP binding protein Rab13 and Rab18, which are with a common CAAX motif and known to regulate the ER-Golgi traffic or lipogenesis. Neither Rce1 transcription nor RCE1 protein level was inhibited by Brefeldin A, which is known to interfere with the ER-Golgi traffic causing Golgi stress. Knocking down Rce1 with RNA interference increased ritonavir and lopinavir-induced cell death as well as expression of Golgi stress response markers, TFE3, HSP47 and GCP60, in both primary mouse hepatocytes and mouse liver, and deteriorated alcohol-induced alanine aminotransferase (ALT) and fatty liver injury in mice. In addition, overexpressing Rab13 or Rab18 in primary human hepatocytes reduced partially the anti-HIV drugs and alcohol-induced Golgi fragmentation, Golgi stress response, and cell death injury. Conclusion: We identified a mechanism linking a host protease and its substrates, small guanosine triphosphate-binding proteins, to the anti-HIV drug-induced Golgi dysfunction, organelle stress response, and fatty liver injury. (Hepatology Communications 2020;4:932-944).

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Rapamycin Rescues Age-Related Changes in Muscle-Derived Stem/Progenitor Cells from Progeroid Mice

Cited by 39 publications

References 82 publications

Aged Tendon Stem/Progenitor Cells Are Less Competent to Form 3D Tendon Organoids Due to Cell Autonomous and Matrix Production Deficits

Aged Tendon Stem/Progenitor Cells Are Less Competent to Form 3D Tendon Organoids Due to Cell Autonomous and Matrix Production Deficits

Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

Ritonavir and Lopinavir Suppress RCE1 and CAAX Rab Proteins Sensitizing the Liver to Organelle Stress and Injury

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