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- Title
Heme oxygenase‐1 affects generation and spontaneous cardiac differentiation of induced pluripotent stem cells.
- Authors
Stepniewski, Jacek; Pacholczak, Tomasz; Skrzypczyk, Aniela; Ciesla, Maciej; Szade, Agata; Szade, Krzysztof; Bidanel, Romain; Langrzyk, Agnieszka; Grochowski, Radoslaw; Vandermeeren, Felix; Kachamakova‐Trojanowska, Neli; Jez, Mateusz; Drabik, Grazyna; Nakanishi, Mahito; Jozkowicz, Alicja; Dulak, Jozef
- Abstract
Abstract: Cellular stress can influence efficiency of iPSCs generation and their differentiation. However, the role of intracellular cytoprotective factors in these processes is still not well known. Therefore, we investigated the effect of HO‐1 (<italic>Hmox1</italic>) or Nrf2 (<italic>Nfe2l2</italic>), two major cytoprotective genes. <italic>Hmox1</italic>–/– fibroblasts demonstrated decreased reprogramming efficiency in comparison to <italic>Hmox1+/+</italic> cells. Reversely, pharmacological enhancement of HO‐1 resulted in higher number of iPSCs colonies. Importantly, elevated level of both p53 and p53‐regulated miR‐34a and 14‐3‐3σ was observed in HO‐1‐deficient fibroblasts whereas downregulation of p53 in these cells markedly increased their reprogramming efficiency. In human fibroblasts HO‐1 silencing also induced p53 expression and affected reprogramming outcome. <italic>Hmox1+/+</italic> and <italic>Hmox1</italic>–/– iPSCs similarly differentiated <italic>in vitro</italic> to cells originating from three germ layers, however, lower number of contracting cells was observed during this process in HO‐1‐deficient cells indicating attenuated cardiac differentiation. Importantly, silencing of <italic>Hmox1</italic> in murine ESC using CRISPR/Cas‐9 editing also impaired their spontaneous cardiac differentiation. Decreased reprogramming efficiency was also observed in Nrf2‐lacking fibroblasts. Reversely, sulforaphane, a Nrf2 activator, increased the number of iPSCs colonies. However, both <italic>Nfe2l2+/+</italic> and <italic>Nfe2l2</italic>–/– iPSCs showed similar pluripotency and differentiation capacity. These results indicate that regulation of HO‐1 expression can further optimize generation and cardiac differentiation of iPSCs. © 2018 IUBMB Life, 70(2):129–142, 2018
- Subjects
HEME oxygenase; INDUCED pluripotent stem cells; CYTOPROTECTION; CELL differentiation; FIBROBLASTS
- Publication
IUBMB Life, 2018, Vol 70, Issue 2, p129
- ISSN
1521-6543
- Publication type
Article
- DOI
10.1002/iub.1711