Different kinds of fat cell progenitors that are found at different anatomical locations may follow different developmental paths. By identifying the progenitors and mapping the paths, which may diverge or sometimes even converge, scientists hope to direct developmental traffic to healthier destinations. For example, scientists would like fat cell progenitors to become mature fat cells that expand in number rather than size. If fat cells expand in size, they may cause fibrosis and inflammation and, ultimately, metabolic diseases such as type 2 diabetes.

At the University of Pennsylvania, scientists working in mice and human tissue have identified several classes of adipocyte progenitor cells, some of which reside in a recently discovered anatomical niche. The results may help inform the development of targeted approaches to prevent metabolic diseases.

Metabolic health relies on the ability of adipose tissue progenitor cells (APCs) to become fully fledged fat cells. However, the cellular mechanisms underlying the formation of adipocytes, and the APCs from which they are derived, are incompletely understood.

To better understand the mechanisms behind adipocyte formation, a team of University of Pennsylvania scientists led by Patrick Seale, PhD, used single-cell RNA sequencing to identify and profile progenitor cells from the rapidly developing white adipose tissue of 12-day old mice. The team identified three classes of APCs: interstitial progenitor cells, preadipocytes, and group 3 cells. Additional experiments revealed that two general classes of APCs analogous to those found in mice are present in subcutaneous fat tissue in humans.

Detailed findings appeared April 26 in Science, in an article titled, “Identification of a mesenchymal progenitor cell hierarchy in adipose tissue.” The article described how Seale and colleagues 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.

“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,” the article’s authors wrote. “Targeting one or more of these cell populations may be beneficial for promoting adaptive hyperplastic adipose growth to ameliorate metabolic disease.”

The results suggest a general paradigm for adipogenesis in both mice and humans, the authors indicated. Intriguingly, in mice, one of the identified progenitor cells—marked by a protein called DPP4—was found in the reticulum interstitium (RI). This recently recognized anatomical niche is a fluid-filled network of collagen and elastin fibers that surrounds many organs.

“Given that the RI exists in multiple human tissues, an intriguing possibility is that the RI represents a new stem cell niche for fat tissue and beyond,” noted the University of Edinburgh’s You-Ying Chau, PhD, and William Cawthron, PhD, in a Perspective article (“Fat cell progenitors get singled out”) about the Seale team’s work. They also discuss how the work compares to recent efforts to understand adipose tissue progenitor cells.

“Our results,” the Seale team concluded, “raise the possibility that in addition to serving as a reservoir for adipocyte progenitor cells in fat depots, the RI plays important roles in the development and regeneration of other tissues. Lastly, the identification of functionally distinct precursor populations could potentially inform the development of more targeted approaches to promote metabolically beneficial adipose growth.”

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