Research Article

Identification of a mesenchymal progenitor cell hierarchy in adipose tissue

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Science  26 Apr 2019:
Vol. 364, Issue 6438, eaav2501
DOI: 10.1126/science.aav2501

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A singular focus on fat

Fatty tissue can expand in two ways: through increases in the size of individual adipocytes or through increases in the number of adipocytes. The former process promotes metabolic disease, and the latter protects against it. Merrick et al. used single-cell RNA sequencing to define the hierarchy of mesenchymal progenitor cells that give rise to adipose tissue in mice and humans (see the Perspective by Chau and Cawthorn). They found that progenitor cells expressing a protein called DPP4 give rise to two distinct types of preadipocytes in response to different signals. The DPP4 progenitors reside in a fluid-filled network of collagen and elastin fibers surrounding adipose tissue. In principle, therapeutic interventions that increase progenitor cell differentiation into adipocytes could ameliorate metabolic disease.

Science, this issue p. eaav2501; see also p. 328

Structured Abstract


Adipose tissue is a highly plastic organ that plays a central role in regulating whole-body energy metabolism. The capacity for adipocytes to store chemical energy in lipid droplets protects other organs against the toxic effects of ectopic lipid deposition. In the setting of chronic nutritional excess, such as obesity, adipose tissue expands through increases in fat cell size (hypertrophy) and/or fat cell number (hyperplasia). Adipocyte hypertrophy causes fibrosis and inflammation, thereby promoting metabolic disease. Conversely, hyperplastic growth, mediated by the differentiation of progenitor cells into new adipocytes, is critical for preserving adipose tissue function and protecting against metabolic disease. However, the precise cell types, lineage dynamics, and mechanisms governing the development of adipocytes are incompletely understood.


Adipose mesenchymal progenitors constitute a heterogeneous pool of diverse cell types. Previous attempts to characterize these cells have relied on nonspecific mesenchymal markers and candidate lineage marker genes. We used single-cell RNA sequencing to identify distinct types of progenitor cells in murine and human adipose tissues and to predict lineage relationships in an unbiased manner. Functional assessments of these cell types in vitro and in vivo define a mesenchymal cell hierarchy involved in adipocyte formation.


Single-cell RNA sequencing and cell trajectory analyses identified a lineage hierarchy consisting of several distinct mesenchymal cell types in murine and human adipose. Dipeptidyl peptidase–4–expressing (DPP4+) cells are highly proliferative and multipotent progenitors that are relatively resistant to differentiation into adipocytes. Intercellular adhesion molecule–1–expressing (ICAM1+) cells are committed preadipocytes that express Pparg and are poised to differentiate into mature adipocytes with minimal stimulation. CD142+/Clec11a+ cells represent a distinct adipogenic population in murine subcutaneous adipose that shares many properties with ICAM1+ preadipocytes. In vivo cell transplantation studies showed that DPP4+ progenitors give rise to both ICAM1+ and CD142+ preadipocytes before differentiation into mature adipocytes. DPP4+ cells depend on transforming growth factor–β (TGFβ) signaling to maintain their progenitor identity, whereas ICAM1+ preadipocytes are refractory to the proliferative and anti-adipogenic actions of the TGFβ pathway. Obesity and insulin resistance lead to a depletion of DPP4+ mesenchymal progenitors and a reduction in the adipogenic differentiation competency of preadipocytes, specifically in visceral white adipose tissue. Single-cell analysis of human subcutaneous adipose tissue revealed distinct DPP4+ and ICAM1+ populations that displayed functional properties similar to those of the analogous mouse populations. Histological examination of murine subcutaneous adipose tissue showed that ICAM1+ preadipocytes are intercalated between mature adipocytes, occupying a perivascular niche. The DPP4+ progenitor cells are localized in an anatomically distinct niche surrounding the adipose depot, which we term the reticular interstitium.


Our studies define a developmental hierarchy of adipose progenitors consisting of DPP4+ interstitial progenitors that give rise to committed ICAM1+ and CD142+ preadipocytes, which are poised to differentiate into mature adipocytes. Targeting one or more of these cell populations may be beneficial for promoting adaptive hyperplastic adipose growth to ameliorate metabolic disease. A key finding from this work is that adipose progenitor cells reside in the reticular interstitium, a recently appreciated, but not well-studied, fluid-filled network of collagen and elastin fibers that encases many organs, including adipose depots. Our results raise the possibility that DPP4+ cells, in addition to serving as progenitor cells for adipocytes in fat depots, may play important roles in the development and regeneration of other tissues.

DPP4+ progenitors reside in the reticular interstitium and give rise to committed preadipocytes.

DPP4+ multipotent progenitor cells give rise to ICAM1+ and CD142+ committed preadipocytes, which are poised to differentiate into mature adipocytes (top). Committed preadipocytes (green) are intercalated between mature adipocytes, whereas DPP4+ progenitors (red) reside in the reticular interstitium, an anatomically distinct fluid-filled network of collagen and elastin fibers that encases many organs, including adipose depots.


Metabolic health depends on the capacity of adipose tissue progenitor cells to undergo de novo adipogenesis. The cellular hierarchy and mechanisms governing adipocyte progenitor differentiation are incompletely understood. Through single-cell RNA sequence analyses, we show that the lineage hierarchy of adipocyte progenitors consists of distinct mesenchymal cell types that are present in both mouse and human adipose tissues. Cells marked by dipeptidyl peptidase–4 (DPP4)/CD26 expression are highly proliferative, multipotent progenitors. During the development of subcutaneous adipose tissue in mice, these progenitor cells give rise to intercellular adhesion molecule–1 (ICAM1)/CD54–expressing (CD54+) committed preadipocytes and a related adipogenic cell population marked by Clec11a and F3/CD142 expression. Transforming growth factor–β maintains DPP4+ cell identity and inhibits adipogenic commitment of DPP4+ and CD142+ cells. Notably, DPP4+ progenitors reside in the reticular interstitium, a recently appreciated fluid-filled space within and between tissues, including adipose depots.

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