FOXO3-engineered human mesenchymal progenitor cells efficiently promote cardiac repair after myocardial infarction

Lei, Jinghui; Wang, Si; Wang, Kang; Chu, Qun; Liu, Zunpeng; Sun, Liang; Ji, Yun Bae; Esteban, Concepción Rodrı́guez; Yao, Yan; Belmonte, Juan Carlos Izpisúa; Chan, Piu; Liu, Guanghui; Zhang, Weiqi; Song, Moshi; Qu, Jing

doi:10.1007/s13238-020-00779-7

Cited by 34 publications

(17 citation statements)

References 16 publications

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“…Myocardial infarction was induced as previously described 70 , 71 . First, male C57BL/6 J mice (8 weeks old) were anesthetized with 2% isoflurane in an inducing chamber and immobilized on the surgical board with medical tapes.…”

Section: Methodsmentioning

confidence: 99%

Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor

Liu

Geng

et al. 2022

Cell Discov

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Regenerative capacity declines throughout evolution and with age. In this study, we asked whether metabolic programs underlying regenerative capability might be conserved across species, and if so, whether such metabolic drivers might be harnessed to promote tissue repair. To this end, we conducted metabolomic analyses in two vertebrate organ regeneration models: the axolotl limb blastema and antler stem cells. To further reveal why young individuals have higher regenerative capacity than the elderly, we also constructed metabolic profiles for primate juvenile and aged tissues, as well as young and aged human stem cells. In joint analyses, we uncovered that active pyrimidine metabolism and fatty acid metabolism correlated with higher regenerative capacity. Furthermore, we identified a set of regeneration-related metabolite effectors conserved across species. One such metabolite is uridine, a pyrimidine nucleoside, which can rejuvenate aged human stem cells and promote regeneration of various tissues in vivo. These observations will open new avenues for metabolic intervention in tissue repair and regeneration.

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Section: Methodsmentioning

confidence: 99%

Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor

Liu

Geng

et al. 2022

Cell Discov

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“…Among the most significantly upregulated genes in the resistant cells, we found insulin growth factor-2 ( IGF2 ) ( Figure 2 C). Since IGF2 has been shown to play an important role in cancer progression by limiting therapy efficacy (reviewed in Reference [ 44 ]) and has also been shown to be associated with FOXO3 activity in mesenchymal progenitor cells [ 45 ], we utilized the TCGA RNAseq data of HNC patients to explore whether expression of FOXO family members is associated with IGF2 expression. Spearman coefficient and the −log 10 p -value plot show the correlation between IGF2 and three FOXO members ( Figure 2 D).…”

Section: Resultsmentioning

confidence: 99%

IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer

Badarni

Prasad

Golden

et al. 2021

Cancers

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Over 50% of human papilloma positive head-and-neck cancer (HNCHPV+) patients harbor genomic-alterations in PIK3CA, leading to hyperactivation of the phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) pathway. Nevertheless, despite PI3K pathway activation in HNCHPV+ tumors, the anti-tumor activities of PI3K pathway inhibitors are moderate, mostly due to the emergence of resistance. Thus, for potent and long-term tumor management, drugs blocking resistance mechanisms should be combined with PI3K inhibitors. Here, we delineate the molecular mechanisms of the acquisition of resistance to two isoform-selective inhibitors of PI3K (isiPI3K), alpelisib (BYL719) and taselisib (GDC0032), in HNCHPV+ cell lines. By comparing the transcriptional landscape of isiPI3K-sensitive tumor cells with that of their corresponding isiPI3K-acquired-resistant tumor cells, we found upregulation of insulin growth factor 2 (IGF2) in the resistant cells. Mechanistically, we show that upon isiPI3K treatment, isiPI3K-sensitive tumor cells upregulate the expression of IGF2 to induce cell proliferation via the activation of the IGF1 receptor (IGF1R). Stimulating tumor cells with recombinant IGF2 limited isiPI3K efficacy and released treated cells from S phase arrest. Knocking-down IGF2 with siRNA, or blocking IGF1R with AEW541, resulted in superior anti-tumor activity of isiPI3K in vitro and ex vivo. In vivo, the combination of isiPI3K and IGF1R inhibitor induced stable disease in mice bearing either tumors generated by the HNCHPV+ UM-SCC47 cell line or HPV+ patient-derived xenografts. These findings indicate that IGF2 and the IGF2/IGF1R pathway may constitute new targets for combination therapies to enhance the efficacy of PI3K inhibitors for the treatment of HNCHPV+.

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“…Genetic enhancement has been explored as a method for improving the regenerative capacity of hMSCs, as well as reducing the risk of tumorigenesis. 50 Nuclear factor erythroid-2-like 2 ( NRF2 ) mediates the antioxidative response, and could potentially promote rejuvenation of hMSCs. Leveraging gene editing, a single-nucleotide variation (A245G) was introduced into NRF2 .…”

Section: Rejuvenation Of Adult Stem Cellsmentioning

confidence: 99%

“… 52 In addition, delivery of FOXO3 genetic enhanced hMSCs into the myocardial ischemia mouse model reversed increased pro-inflammatory factor levels, reduced cardiac fibrosis, and improved heart function. 50 Collectively, genetic enhancement of certain functional genes in adult stem cells protects stem cells from aging and improves regeneration capacity.…”

Section: Rejuvenation Of Adult Stem Cellsmentioning

confidence: 99%

Rejuvenation of Tissue Stem Cells by Intrinsic and Extrinsic Factors

Cai

Wang

et al. 2022

Stem Cells Translational Medicine

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Stem cell therapies, including stem cell transplantation and rejuvenation of stem cells in situ, are promising avenues for tackling a broad range of diseases. Stem cells can both self-renew and differentiate into other cell types, and play a significant role in the regulation of tissue homeostasis and regeneration after cell degeneration or injury. However, stem cell exhaustion or dysfunction increases with age and impedes the normal function of multiple tissues and systems. Thus, stem cell therapies could provide a solution to aging and age-associated diseases. Here, we discuss recent advances in understanding the mechanisms that regulate stem cell regeneration. We also summarize potential strategies for rejuvenating stem cells that leverage intrinsic and extrinsic factors. These approaches may pave the way toward therapeutic interventions aiming at extending both health and life span.

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FOXO3-engineered human mesenchymal progenitor cells efficiently promote cardiac repair after myocardial infarction

Cited by 34 publications

References 16 publications

Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor

Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor

IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer

Rejuvenation of Tissue Stem Cells by Intrinsic and Extrinsic Factors

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