Navigating the Adipocyte Precursor Niche: Cell-Cell Interactions, Regulatory Mechanisms and Implications for Adipose Tissue Homeostasis

Abstract

Support for stem cell self-renewal and differentiation hinges upon the intricate microenvironment termed the stem cell 'niche'. Within the adipose tissue stem cell niche, diverse cell types, such as endothelial cells, immune cells, mural cells, and adipocytes, intricately regulate the function of adipocyte precursors. These interactions, whether direct or indirect, play a pivotal role in governing the balance between self-renewal and differentiation of adipocyte precursors into adipocytes. The mechanisms orchestrating the maintenance and coordination of this niche are still in the early stages of comprehension, despite their crucial role in regulating adipose tissue homeostasis. The complexity of understanding adipocyte precursor renewal and differentiation is amplified due to the challenges posed by the absence of suitable surface receptors for identification, limitations in creating optimal ex vivo culture conditions for expansion and constraints in conducting in vivo studies. This review delves into the current landscape of knowledge surrounding adipocyte precursors within the adipose stem cell niche. We will review the identification of adipocyte precursors, the cell-cell interactions they engage in, the factors influencing their renewal and commitment toward adipocytes and the transformations they undergo during instances of obesity.

Keywords: ASCs; Adipogenesis; Adipogenic precursors; Adipose-derived stem cells; Brown adipose; Diabetes; Metabolic syndrome; Obesity.

Figure 1:. Structure and interplay within the adipose tissue microenvironment.

(A) Adipose tissue consists of clusters of adipocytes arranged in lobules, which are separated from each other by ECM that forms the septa (B). In addition to the septa lining the outside of the lobule, the internal stroma also contains a distinct ECM compartment (C). (D) ECM within the stroma of the lobule contains CD34+/MSCA1+/CD271- APs that are highly adipogenic and positioned between adipocytes or adjacent to the vasculature. (E) ECM within the septa contains CD34+/MSCA1-/CD271+ myofibroblasts that may aid in formation of the fibrous septa and contribute to fibrosis during obesity. (F) PDGFRβ+ mural cells located in the vessel walls may harbor adipogenic activity, but recent data contradicts this and suggests PDGFRα+/β+ APs (G) located within the vessel wall adventitia contribute to the majority of adipocytes found in white, beige and brown adipocytes (H). (I) CD206+ M2 macrophages play a role in maintenance of APs through secretion of anti-adipogenic TGFβ1, which prevents exhaustion of the AP pool by limiting excessive proliferation and premature senescence. (J) IL-4 and BMP4 represent two potential factors that may decrease the proportion of M1 macrophages in adipose tissue in favor of anti-inflammatory M2 macrophages, which play a role in adipose tissue browning, protection from high-fat diet-induced obesity and improved metabolism. (K) FSP1+ fibroblasts found in the loose connective tissue outside the vessel wall rely on WNT signaling for proper function and lack adipogenic potential (red X). They contribute to the renewal and differentiation potential of APs through the secretion of PDGF-BB and remodeling of the ECM. (L) CD34+/CD24+ ASCs express markers of pluripotency (OCT4, NANOG and SOX2) and undergo FGF2 mediated self-renewal. BMP ligands can induce multipotent ASCs to form committed APs (CD24-) that express adipocyte lineage-selective genes such as PPARγ. Figure modified from [216].

Figure 2:. Interactions between macrophages and adipogenic precursors.

(A) Eosinophils secrete IL-4 and IL-13 that polarize macrophages toward an M2 fate, potentially contributing to browning and the formation of beige adipocytes through catecholamine secretion (B). (C) Secretion of IL-4 from eosinophils and potentially M2 macrophages may directly impact adipogenic precursors to enhance their capacity to undergo beige adipogenesis. (D) TGFβ1 expressed by CD206+ M2 macrophages hinders the proliferation of PDGFRα+ adipogenic precursors to prevent premature senescence and precursor cell exhaustion. (E) BMP4 derived from adipogenic precursors stimulates the proliferation of CD206+ M2 macrophages while inhibiting M1 macrophages, resulting in a substantial rise in M2 macrophage numbers that may lead to increased browning of WAT. (F) ASCs from obese and type 2 diabetic individuals exhibit up-regulation of inflammatory genes that may contribute to adipose tissue inflammation and insulin resistance by attracting and directing macrophages towards the M1 subtype.