PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes

Wickramasinghe, Nadeera M.; Sachs, David; Shewale, Bhavana; Gonzalez, David M.; Dhanan-Krishnan, Priyanka; Torre, Denis; LaMarca, Elizabeth A.; Raimo, Serena; Dariolli, Rafael; Serasinghe, Madhavika N.; Mayourian, Joshua; Sebra, Robert; Beaumont, Kristin G.; Iyengar, Srinivas; French, Deborah L.; Hansen, Arne; Eschenhagen, Thomas; Chipuk, Jerry E.; Sobie, Eric A.; Jacobs, Adam; Akbarian, Schahram; Ischiropoulos, Harry; Ma’ayan, Avi; Houten, Sander M.; Costa, Kevin D.; Dubois, Nicole

doi:10.1016/j.stem.2022.02.011

Cited by 39 publications

(26 citation statements)

References 108 publications

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“…qRT‐PCR and Western blotting experiments showed that the expression of ACOX1 was pronouncedly decreased in cells with PTPRO knockdown and increased in those with PTPRO overexpression (Figures 6A–6B ; Supplementary Figure S6A‐B ), implying that PTPRO might modulate the expression of ACOX1 transcriptionally. Previous studies reported that PPARs could play important roles in lipid metabolism and are critical regulators in FAO [ 32 , 33 ]. We hypothesized that PTPRO may regulate ACOX1 expression via PPARs.…”

Section: Resultsmentioning

confidence: 99%

“…Consistently, we demonstrated that ACOX1‐mediated FAO could exert a protective role in CRC initiation and growth. Researches have revealed that PPARs were essential transcriptional regulators for FAO, for which PPARα and PPARδ were shown to induce FAO, thus promoting tumorigenesis [ 32 , 33 ]. Additionally, PPARα has been reported to be able to sustain the growth of cancer cells [ 57 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

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PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism

Dai

Xiang

Han

et al. 2022

Cancer Communications

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Background Abnormal expression of protein tyrosine phosphatases (PTPs) has been reported to be a crucial cause of cancer. As a member of PTPs, protein tyrosine phosphatase receptor type O (PTPRO) has been revealed to play tumor suppressive roles in several cancers, while its roles in colorectal cancer (CRC) remains to be elucidated. Hence, we aimed to explore the roles and mechanisms of PTPRO in CRC initiation and progression. Methods The influences of PTPRO on the growth and liver metastasis of CRC cells and the expression patterns of different lipid metabolism enzymes were evaluated in vitro and in vivo. Molecular and biological experiments were conducted to uncover the underpinning mechanisms of dysregulated de novo lipogenesis and fatty acid β‐oxidation. Results PTPRO expression was notably downregulated in CRC liver metastasis compared to the primary cancer, and such a downregulation was associated with poor prognosis of patients with CRC. PTPRO silencing significantly promoted cell growth and liver metastasis. Compared with PTPRO wild‐type mice, PTPRO‐knockout mice developed more tumors and harbored larger tumor loads under treatment with azoxymethane and dextran sulfate sodium. Gene set enrichment analysis revealed that PTPRO downregulation was significantly associated with the fatty acid metabolism pathways. Blockage of fatty acid synthesis abrogated the effects of PTPRO silencing on cell growth and liver metastasis. Further experiments indicated that PTPRO silencing induced the activation of the AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling axis, thus promoting de novo lipogenesis by enhancing the expression of sterol regulatory element‐binding protein 1 (SREBP1) and its target lipogenic enzyme acetyl‐CoA carboxylase alpha (ACC1) by activating the AKT/mTOR signaling pathway. Furthermore, PTPRO attenuation decreased the fatty acid oxidation rate by repressing the expression of peroxisome proliferator‐activated receptor alpha (PPARα) and its downstream enzyme peroxisomal acyl‐coenzyme A oxidase 1 (ACOX1) via activating the p38/extracellular signal‐regulated kinase (ERK) mitogen‐activated protein kinase (MAPK) signaling pathway. Conclusions PTPRO could suppress CRC development and metastasis via modulating the AKT/mTOR/SREBP1/ACC1 and MAPK/PPARα/ACOX1 pathways and reprogramming lipid metabolism.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism

Dai

Xiang

Han

et al. 2022

Cancer Communications

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“…These results are suggestive of two opposing processes for which a balance must be achieved during advancement to adult stages, namely proliferation versus maturation. Previous studies using single-cell RNA-seq reported increased maturation of iPSC-CMs via strategies including prolonged in vitro differentiation, multilineage organoid culture, activation of hypertrophic signaling, and increased fatty acid metabolism ( DeLaughter et al, 2016 ; Churko et al, 2018 ; Friedman et al, 2018 ; Biendarra-Tiegs et al, 2019 ; Funakoshi et al, 2021 ; Grancharova et al, 2021 ; Silva et al, 2021 ; Wickramasinghe et al, 2022 ). It is well established that iPSC-CMs are highly proliferative compared to their in vivo counterparts.…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomic profiling reveals specific maturation signatures in human cardiomyocytes derived from LMNB2-inactivated induced pluripotent stem cells

Wang

Morgan

Saini

et al. 2022

Front. Cell Dev. Biol.

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Mammalian cardiomyocyte maturation entails phenotypic and functional optimization during the late fetal and postnatal phases of heart development, both processes driven and coordinated by complex gene regulatory networks. Cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) are heterogenous and immature, barely resembling their adult in vivo counterparts. To characterize relevant developmental programs and maturation states during human iPSC-cardiomyocyte differentiation, we performed single-cell transcriptomic sequencing, which revealed six cardiomyocyte subpopulations, whose heterogeneity was defined by cell cycle and maturation states. Two of those subpopulations were characterized by a mature, non-proliferative transcriptional profile. To further investigate the proliferation-maturation transition in cardiomyocytes, we induced loss-of-function of LMNB2, which represses cell cycle progression in primary cardiomyocytes in vivo. This resulted in increased maturation in LMNB2-inactivated cardiomyocytes, characterized by transcriptional profiles related to myofibril structure and energy metabolism. Furthermore, we identified maturation signatures and maturational trajectories unique for control and LMNB2-inactivated cardiomyocytes. By comparing these datasets with single-cell transcriptomes of human fetal hearts, we were able to define spatiotemporal maturation states in human iPSC-cardiomyocytes. Our results provide an integrated approach for comparing in vitro-differentiated cardiomyocytes with their in vivo counterparts and suggest a strategy to promote cardiomyocyte maturation.

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“…For more information on the impact of MM on CM structural maturation and sarcomeric alignment, see Figures 2 , 3 . The transient exposure to lactate as part of metabolic purification of hPSC-CMs was recently shown to induce a long-term transcriptomic shift in the expression of genes involved in the maturation of calcium handling, contractility, and decreased proliferation markers as well as Wnt signaling and PPP ( 25 ).…”

Section: Signaling Pathways Potentially Associated With Human Induced...mentioning

confidence: 99%

“…The treatment of both hPSC-CMs 2D monolayers and engineered heart tissues (EHT; starting 2 weeks after replating of day 20 CMs for a duration of 4 weeks treatment) with 2.5 μM GSK0660 (a PPARδ agonist) enhanced fatty acid oxidation, sarcomere alignment, CM size, binucleation, electrophysiology (e.g., action potential duration), and contractility. Still, T-tubule formation, gap junction proteins expression/localization, and some aspects of electrophysiological maturation remains to be investigated in future research ( 25 ).…”

Section: Signaling Pathways Potentially Associated With Human Induced...mentioning

confidence: 99%

Using human induced pluripotent stem cell-derived cardiomyocytes to understand the mechanisms driving cardiomyocyte maturation

Hamledari

Asghari

Jayousi

et al. 2022

Front. Cardiovasc. Med.

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Cardiovascular diseases are the leading cause of mortality and reduced quality of life globally. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a personalized platform to study inherited heart diseases, drug-induced cardiac toxicity, and cardiac regenerative therapy. However, the immaturity of CMs obtained by current strategies is a major hurdle in utilizing hiPSC-CMs at their fullest potential. Here, the major findings and limitations of current maturation methodologies to enhance the utility of hiPSC-CMs in the battle against a major source of morbidity and mortality are reviewed. The most recent knowledge of the potential signaling pathways involved in the transition of fetal to adult CMs are assimilated. In particular, we take a deeper look on role of nutrient sensing signaling pathways and the potential role of cap-independent translation mediated by the modulation of mTOR pathway in the regulation of cardiac gap junctions and other yet to be identified aspects of CM maturation. Moreover, a relatively unexplored perspective on how our knowledge on the effects of preterm birth on cardiovascular development can be actually utilized to enhance the current understanding of CM maturation is examined. Furthermore, the interaction between the evolving neonatal human heart and brown adipose tissue as the major source of neonatal thermogenesis and its endocrine function on CM development is another discussed topic which is worthy of future investigation. Finally, the current knowledge regarding transcriptional mediators of CM maturation is still limited. The recent studies have produced the groundwork to better understand CM maturation in terms of providing some of the key factors involved in maturation and development of metrics for assessment of maturation which proves essential for future studies on in vitro PSC-CMs maturation.

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PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes

Cited by 39 publications

References 108 publications

PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism

PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism

Single-cell transcriptomic profiling reveals specific maturation signatures in human cardiomyocytes derived from LMNB2-inactivated induced pluripotent stem cells

Using human induced pluripotent stem cell-derived cardiomyocytes to understand the mechanisms driving cardiomyocyte maturation

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