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Cross-anatomical single-cell definition and characterization of human adipose progenitor niche

Radiana Ferrero

Adipose tissue is a key metabolic and highly-dynamic organ whose dysregulation may cause clinical conditions of concern such as obesity and lipodystrophy. Its function varies based on the anatomy, in fact, visceral adipose tissue expansion carries a greater risk of life-threatening associated comorbidities than subcutaneous expansion. Among the responsible for adipose tissue plasticity are the adipose-derived stem and progenitor cells (ASPCs) which can commit to form new mature adipocytes even in a post-developmental adult organism. The advent of scRNA-seq techniques allowed to deline-ate a clear and unbiased picture of the murine ASPC landscape across depots, unraveling subpopulations with distinct functional properties and even non- and anti-adipogenic features, however a similar depth of understanding is still lack-ing in humans. This work focuses on defining the human ASPC niche composition and equilibrium across four different depots (Subcuta-neous (SC), Omental (OM), Perirenal (PR) and Mesocolic (MC)) and over more than 75 individuals of various BMIs. We took advantage of bulk and scRNA-seq techniques to explore hASPC heterogeneity then functionalize our findings in vitro over 30 donors. We found that two main populations, the highly-proliferative adipose stem cells and highly-adipogenic pre-adipocytes, are ubiquitously present in all analyzed depots but their relative proportions display a depot-specific and BMI-dependent distribution. Despite their omnipresence, these subpopulations still exhibited depot-specific gene expression patterns, likely reflecting distinct AT properties. Five minor subpopulations are also shared across depots and have specific gene expression patterns resembling populations previously described in mice. We further identified two OM-specific meso-thelial cell populations, cobblestone in morphology, out of which one highly expresses and secretes IGFBP2 (Insulin-like growth factor binding protein 2). This OM-specific IGFBP2+ population constitutes 2-5% of the non-immune, non-endothelial OM stromal vascular fraction depending on the donor's BMI, appears to transition between mesothelial and mesenchymal cell states and inhibits the adipogenic capacity of hASPCs in a depot-specific manner through IGFBP2 secre-tion and integrin receptor signaling. Altogether, our in-depth characterization of hASPC heterogeneity and function not only highlights the cellular uniqueness of different adipose niches but also identifies a new mechanism underlying the limited adipogenic capacity of OM hASPCs by uncovering an OM-specific IGFBP2+ mesothelial-like cell population that negatively regulates hASPC adipogenesis through IGFBP2 signaling. Further dissecting the precise mechanism of negative regulation in adipogenesis may lead to the discovery of new druggable targets to combat excessive adipose tissue expansion.

EPFL2023

Mammalian adipogenesis regulator (Areg) cells use retinoic acid signalling to be non- and anti-adipogenic in age-dependent manner

Daniel Alpern, Bart Deplancke, Radiana Ferrero, Horia Hashimi, Maria Litovchenko, Pernille Yde Rainer, Julie Marie Russeil, Magda Zachara

Adipose stem and precursor cells (ASPCs) give rise to adipocytes and determine the composition and plasticity of adipose tissue. Recently, several studies have demonstrated that ASPCs partition into at least three distinct cell subpopulations, including the enigmatic CD142(+) cells. An outstanding challenge is to functionally characterise this population, as discrepant properties, from adipogenic to non- and anti-adipogenic, have been reported for these cells. To resolve these phenotypic ambiguities, we characterised mammalian subcutaneous CD142(+) ASPCs across various experimental conditions, demonstrating that CD142(+) ASPCs exhibit high molecular and phenotypic robustness. Specifically, we find these cells to be firmly non- and anti-adipogenic both in vitro and in vivo, with their inhibitory signals also impacting adipogenic human cells. However, these CD142(+) ASPC-specific properties exhibit surprising temporal phenotypic alterations, and emerge only in an age-dependent manner. Finally, using multi-omic and functional assays, we show that the inhibitory nature of these adipogenesis-regulatory CD142(+) ASPCs (Aregs) is driven by specifically expressed secretory factors that cooperate with the retinoic acid signalling pathway to transform the adipogenic state of CD142(-) ASPCs into a non-adipogenic, Areg-like state.

WILEY2022

Toward a Consensus View of Mammalian Adipocyte Stem and Progenitor Cell Heterogeneity

Bart Deplancke, Radiana Ferrero, Pernille Yde Rainer

White adipose tissue (WAT) is a cellularly heterogeneous endocrine organ that not only serves as an energy reservoir, but also actively participates in metabolic homeostasis. Among the main constituents of adipose tissue are adipocytes, which arise from adipose stem and progenitor cells (ASPCs). While it is well known that these ASPCs reside in the stromal vascular fraction (SVF) of adipose tissue, their molecular heterogeneity and functional diversity is still poorly understood. Driven by the resolving power of single-cell transcriptomics, several recent studies provided new insights into the cellular complexity of ASPCs among different mammalian fat depots. In this review, we present current knowledge on ASPCs, their population structure, hierarchy, fat depot-specific nature, function, and regulatory mechanisms, and discuss not only the similarities, but also the differences between mouse and human ASPC biology.

ELSEVIER SCIENCE LONDON2020