Dissecting human adipose tissue heterogeneity using single-cell omics technologies

Abstract

Single-cell omics technologies that profile genes (genomic and epigenomic) and determine the abundance of mRNA (transcriptomic), protein (proteomic and secretomic), lipids (lipidomic), and extracellular matrix (matrisomic) support the dissection of adipose tissue heterogeneity at unprecedented resolution in a temporally and spatially defined manner. In particular, cell omics technologies may provide innovative biomarkers for the identification of rare specific progenitor cell subpopulations, assess transcriptional and proteomic changes affecting cell proliferation and immunomodulatory potential, and accurately define the lineage hierarchy and differentiation status of progenitor cells. Unraveling adipose tissue complexity may also provide for the precise assessment of a dysfunctional state, which has been associated with cancer, as cancer-associated adipocytes play an important role in shaping the tumor microenvironment supporting tumor progression and metastasis, obesity, metabolic syndrome, and type 2 diabetes mellitus. The information collected by single-cell omics has relevant implications for regenerative medicine because adipose tissue is an accessible source of multipotent cells; alternative cell-free approaches, including the use of adipose tissue stromal cell-conditioned medium, extracellular vesicles, or decellularized extracellular matrix, are clinically valid options. Subcutaneous white adipose tissue, which is generally harvested via liposuction, is highly heterogeneous because of intrinsic biological variability and extrinsic inconsistencies in the harvesting and processing procedures. The current limited understanding of adipose tissue heterogeneity impinges on the definition of quality standards appropriate for clinical translation, which requires consistency and uniformity of the administered product. We review the methods used for dissecting adipose tissue heterogeneity and provide an overview of advances in omics technology that may contribute to the exploration of heterogeneity and dynamics of adipose tissue at the single-cell level.

1. Introduction

Over the last decades, the therapeutic potential of autologous adipose tissue-derived material transplantation has been explored in several regenerative medicine clinical trials [1]. Most of the preclinical and translational research employed adipose tissue-derived stromal cells isolated by enzymatic digestion of white adipose tissue (WAT), mainly obtained from subcutaneous fat depots [2, 3]; the regenerative potential of mechanically manipulated adipose tissue has also been evaluated [4]; moreover, adipose tissue paracrine factors, including extracellular vesicles (EVs) and cell-conditioned medium, and decellularized extracellular matrix, have also been considered as cell-free therapeutics [5], in order to circumvent the limited transplanted cell viability in the hypoxic microenvironment at the administration site [6, 7].

Therapeutic efficacy of adipose tissue derivatives in regenerative medicine, dermatology, plastic and aesthetic surgery procedures has been ascribed to both the action of resident multipotent stromal cells and paracrine signals. Nonetheless, inconsistencies in the methods used for adipose tissue manipulation currently limit the reproducible therapeutic efficacy of adipose tissue derivatives, but progressive efforts in the standardization of the procedures will eventually address this issue. Another source of variability is the intrinsic biological heterogeneity, which requires extensive studies at the cellular level to unravel the biological properties, function and clinical potential of adipose tissue derivatives [8]. Single-cell technologies measure the abundance of molecules in individual cells and represent a unique tool to finely dissect tissue cellular and functional heterogeneity, which has been more extensively used for the analysis of the human tumor microenvironment [9].