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

Abstract

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.Adipose Stem and Progenitor Cells: The Adipocytes-To-Be WAT (see Glossary) comprises multiple anatomic entities across the body (e.g., subcutaneous versus visceral) that are composed of loose connective tissue and that feature adipocytes as their fundamental unit. The connective tissue surrounding adipocytes contains the stromal vascular fraction (SVF) and harbors adipose stem and progenitor cells (ASPCs), which are the cells that give birth to mature adipocytes, together with immune cells and vasculature, which assure overall tissue homeostasis.

Mammalian adipogenesis regulators (Aregs) exhibit robust non- and anti-adipogenic properties that arise with age and involve retinoic acid signalling

“…Fig. 1 , Ferrero et al, 2020). One of these three main ASPC clusters, characterized by high and specific F3 (coding for CD142) gene expression, proved to be highly robust and stable across increasing clustering resolution ( Fig.…”

“…Although adipogenesis is one of the best-studied cell differentiation paradigms (Rosen and Spiegelman, 2014), we still have limited knowledge of the in vivo origin and composition of adipose stem and precursor cells (ASPCs, (Ferrero, Rainer and Deplancke, 2020)). This is partially due to the highly heterogeneous and unstructured nature of adipose tissue depots, which are present in multiple anatomical locations (including subcutaneous and visceral white adipose tissue) and consist of a mixture of different cell types (Cristancho and Lazar, 2011), whose origin and identity differ between distinct fat depots (Cleal, Aldea and Chau, 2017).…”

“…Driven by the resolving power of single-cell RNA-sequencing (scRNA-seq), several studies have recently investigated and confirmed mammalian ASPC heterogeneity (Burl et al , 2018; Hepler et al , 2018; Schwalie et al , 2018; Cho, Lee and Doles, 2019; Gu et al , 2019; Merrick et al , 2019; Spallanzani et al , 2019; Sárvári et al , 2021). Our own integrative analysis of publicly available scRNA-seq data has thereby allowed the compiling of an ASPC subpopulation consensus based on the fact that the three main identified subpopulations exhibit a remarkable molecular consistency throughout the analysed datasets (Ferrero, Rainer and Deplancke, 2020). These subpopulations include adipose stem-like cells with high expression of Cd55 and Dpp4 , pre-adipocyte-like cells with high Aoc3 and Icam1 expression, and a rather enigmatic, third population characterized by high F3 (coding for CD142) and Clec11a expression.…”

“…This is why further studies are warranted that explore its existence as well as its molecular and functional properties, especially in light of recent, divergent findings showing that CD142+ ASPCs are in fact adipogenic (Merrick et al , 2019). The reasons for these functional discrepancies between studies have remained unclear but are hypothesized to reflect differences in cell isolation and sorting criteria, antibodies, culturing conditions, sex or age (Merrick et al , 2019; Ferrero, Rainer and Deplancke, 2020; Corvera, 2021).…”

Adipocytes Are the Control Tower That Manages Adipose Tissue Immunity by Regulating Lipid Metabolism

“…ASCs are composed of heterogeneous populations and each population has unique characteristics. ASCs are largely divided into adipogenic and non-adipogenic subtypes ( 91 ). Adipogenic ASCs preferentially differentiate into adipocytes in response to excess energy, which increases energy storage capacity of adipose tissue.…”