Role of Heme-Oxygenase-1 in Biology of Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells

Jez, Mateusz; Martyniak, Alicja; Andrysiak, Kalina; Mucha, Olga; Szade, Krzysztof; Kania, Alan; Chrobok, Łukasz; Palus-Chramiec, Katarzyna; Sanetra, Anna Magdalena; Lewandowski, M.H.; Pośpiech, Ewelina; Stępniewski, Jacek; Dulak, Józef

doi:10.3390/cells10030522

Cited by 5 publications

(5 citation statements)

References 55 publications

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“…Thus, to further validate the activity of AC27 in a more complex cellular assembly, we used the human induced pluripotent stem cells (hiPSC)-derived pancreatic organoids. We used a previously described hiPSC line generated from the peripheral blood mononuclear cells with non-integrating Sendai vectors for that purpose [ 54 , 55 ]. The hiPSC differentiation and islet organoid formation depends on transcriptional gene regulation involved in pancreas development and various growth factors and stem cell culture ( Figure S8a ).…”

Section: Resultsmentioning

confidence: 99%

DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis

Barzowska

Pucelik

Pustelny

et al. 2021

Cells

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The rising prevalence of diabetes is threatening global health. It is known not only for the occurrence of severe complications but also for the SARS-Cov-2 pandemic, which shows that it exacerbates susceptibility to infections. Current therapies focus on artificially maintaining insulin homeostasis, and a durable cure has not yet been achieved. We demonstrate that our set of small molecule inhibitors of DYRK1A kinase potently promotes β-cell proliferation, enhances long-term insulin secretion, and balances glucagon level in the organoid model of the human islets. Comparable activity is seen in INS-1E and MIN6 cells, in isolated mice islets, and human iPSC-derived β-cells. Our compounds exert a significantly more pronounced effect compared to harmine, the best-documented molecule enhancing β-cell proliferation. Using a body-like environment of the organoid, we provide a proof-of-concept that small–molecule–induced human β-cell proliferation via DYRK1A inhibition is achievable, which lends a considerable promise for regenerative medicine in T1DM and T2DM treatment.

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Section: Resultsmentioning

confidence: 99%

DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis

Barzowska

Pucelik

Pustelny

et al. 2021

Cells

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“…Further studies are required to determine whether HO-1 interacts with other transcription factors including Nrf2 which regulates expression of these genes. A previous study comparing Hmox1 deficient and WT induced pluripotent stem cells reported differential gene expression of over 15 enriched biological process GO Terms [ 57 ]. Our study showed congruence of six biological process terms.…”

Section: Discussionmentioning

confidence: 99%

Identification of Heme Oxygenase-1 as a Putative DNA-Binding Protein

et al. 2022

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Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in degrading heme into biliverdin and iron. HO-1 can also enter the nucleus and regulate gene transcription independent of its enzymatic activity. Whether HO-1 can alter gene expression through direct binding to target DNA remains unclear. Here, we performed HO-1 CHIP-seq and then employed 3D structural modeling to reveal putative HO-1 DNA binding domains. We identified three probable DNA binding domains on HO-1. Using the Proteinarium, we identified several genes as the most highly connected nodes in the interactome among the HO-1 gene binding targets. We further demonstrated that HO-1 modulates the expression of these key genes using Hmox1 deficient cells. Finally, mutation of four conserved amino acids (E215, I211, E201, and Q27) within HO-1 DNA binding domain 1 significantly increased expression of Gtpbp3 and Eif1 genes that were identified within the top 10 binding hits normalized by gene length predicted to bind this domain. Based on these data, we conclude that HO-1 protein is a putative DNA binding protein, and regulates targeted gene expression. This provides the foundation for developing specific inhibitors or activators targeting HO-1 DNA binding domains to modulate targeted gene expression and corresponding cellular function.

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“…Oxygen consumption rate (OCR) in primary hepatocytes was measured using Seahorse Bioscience XFe96 Analyzer (Agilent Technologies, Santa Clara, CA, USA) according to our protocol described previously 86 , 87 . Briefly, 1 × 10 5 of live hepatocytes (determined by the trypan blue staining) were plated into Seahorse XFe96-well plates directly after isolation.…”

Section: Methodsmentioning

confidence: 99%

miR-378 affects metabolic disturbances in the mdx model of Duchenne muscular dystrophy

Podkalicka

Mucha

Kaziród

et al. 2022

Sci Rep

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Although Duchenne muscular dystrophy (DMD) primarily affects muscle tissues, the alterations to systemic metabolism manifested in DMD patients contribute to the severe phenotype of this fatal disorder. We propose that microRNA-378a (miR-378) alters carbohydrate and lipid metabolism in dystrophic mdx mice. In our study, we utilized double knockout animals which lacked both dystrophin and miR-378 (mdx/miR-378−/−). RNA sequencing of the liver identified 561 and 194 differentially expressed genes that distinguished mdx versus wild-type (WT) and mdx/miR-378−/− versus mdx counterparts, respectively. Bioinformatics analysis predicted, among others, carbohydrate metabolism disorder in dystrophic mice, as functionally proven by impaired glucose tolerance and insulin sensitivity. The lack of miR-378 in mdx animals mitigated those effects with a faster glucose clearance in a glucose tolerance test (GTT) and normalization of liver glycogen levels. The absence of miR-378 also restored the expression of genes regulating lipid homeostasis, such as Acly, Fasn, Gpam, Pnpla3, and Scd1. In conclusion, we report for the first time that miR-378 loss results in increased systemic metabolism of mdx mice. Together with our previous finding, demonstrating alleviation of the muscle-related symptoms of DMD, we propose that the inhibition of miR-378 may represent a new strategy to attenuate the multifaceted symptoms of DMD.

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Role of Heme-Oxygenase-1 in Biology of Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells

Cited by 5 publications

References 55 publications

DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis

DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis

Identification of Heme Oxygenase-1 as a Putative DNA-Binding Protein

miR-378 affects metabolic disturbances in the mdx model of Duchenne muscular dystrophy

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