Functional Human Beige Adipocytes From Induced Pluripotent Stem Cells

Cell–cell and cell–matrix interactions guide organ development and homeostasis by controlling lineage specification and maintenance, but the underlying molecular principles are largely unknown. Here, we show that in human developing cardiomyocytes cell–cell contacts at the intercalated disk connect to remodeling of the actin cytoskeleton by regulating the RhoA‐ROCK signaling to maintain an active MRTF/SRF transcriptional program essential for cardiomyocyte identity. Genetic perturbation of this mechanosensory pathway activates an ectopic fat gene program during cardiomyocyte differentiation, which ultimately primes the cells to switch to the brown/beige adipocyte lineage in response to adipogenesis‐inducing signals. We also demonstrate by in vivo fate mapping and clonal analysis of cardiac progenitors that cardiac fat and a subset of cardiac muscle arise from a common precursor expressing Isl1 and Wt1 during heart development, suggesting related mechanisms of determination between the two lineages.

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“…Human iPSC-derived brown/beige adipocytes were differentiated as previously described (Guenantin et al, 2017).…”

Section: Methodsmentioning

confidence: 99%

Interplay of cell–cell contacts and RhoA/ MRTF ‐A signaling regulates cardiomyocyte identity

et al. 2018

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“…A recent protocol established beige adipocytes from human induced pluripotent cells without gene transfer. Importantly, these cells can form differentiated and vascularized adipose tissue when injected subcutaneously .…”

Section: Conclusion and Outlook For Human Healthmentioning

confidence: 99%

Transcriptional Control of Brown and Beige Fat Development and Function

Shapira

Seale

2018

Obesity

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Adipose tissue, once viewed as an inert organ of energy storage, is now appreciated to be a central node for the dynamic regulation of systemic metabolism. There are three general types of adipose tissue: white, brown, and brown‐in‐white or “beige” fat. All three types of adipose tissue communicate extensively with other organs in the body, including skin, liver, pancreas, muscle, and brain, to maintain energy homeostasis. When energy intake chronically exceeds energy expenditure, obesity and its comorbidities can develop. Thus, understanding the molecular mechanisms by which different types of adipose tissues develop and function could uncover new therapies for combating disorders of energy imbalance. In this review, the recent findings on the transcriptional and chromatin‐mediated regulation of brown and beige adipose tissue activity are highlighted.

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“…Overall, these observations indicated that appropriate culture conditions had to be set up to unlock hPSC-BAP adipogenesis. Ascorbic acid, EGF, hydrocortisone, activin A and IL4 have been shown to regulate hiPSC-BAPs differentiation (8,23,24,32) (see Table 1). However, TGFβ signaling has a pivotal role.…”

Section: Critical Role Of the Tgfβ Pathway In Hipsc-ba Progenitor Difmentioning

confidence: 99%

Human Pluripotent Stem Cells: A Relevant Model to Identify Pathways Governing Thermogenic Adipocyte Generation

Yao¹,

Dani²,

Dani³

2020

Front. Endocrinol.

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Brown and brown-like adipocytes (BAs) are promising cell targets to counteract obesity thanks to their potential to drain and oxidize circulating glucose and triglycerides. However, the scarcity of BAs in human adults is a major limitation for energy expenditure based therapies. Enhanced characterization of BA progenitor cells (BAPs) and identification of critical pathways regulating their generation and differentiation into mature BAs would be an effective way to increase the BA mass. The identification of molecular mechanisms involved in the generation of thermogenic adipocytes is progressing substantially in mice. Much less is known in humans, thus highlighting the need for an in vitro model of human adipocyte development. Pluripotent stem cells (PSCs), i.e., embryonic stem cells and induced pluripotent stem cells, help gain insight into the different phases in the development of multiple cell types. We will discuss the capacity of human PSCs to differentiate into BAs in this review. Several groups, including ours, have reported low spontaneous adipocyte generation from PSCs. However, factors governing the differentiation of induced pluripotent stem cell-derived BA progenitors cells were recently identified, and the TGFβ signaling pathway has a pivotal role. The development of new relevant methods, such as the differentiation of hPSC-BAPs into 3D adipospheres to better mimick the lobular structure of human adipose tissue, will also be discussed. Differentiation of human PSCs into thermogenic adipocytes at high frequency provides an opportunity to characterize new targets for anti-obesity therapy.

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Functional Human Beige Adipocytes From Induced Pluripotent Stem Cells

Cited by 43 publications

References 32 publications

Interplay of cell–cell contacts and RhoA/ MRTF ‐A signaling regulates cardiomyocyte identity

Interplay of cell–cell contacts and RhoA/ MRTF ‐A signaling regulates cardiomyocyte identity

Transcriptional Control of Brown and Beige Fat Development and Function

Human Pluripotent Stem Cells: A Relevant Model to Identify Pathways Governing Thermogenic Adipocyte Generation

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