Project: Mesenchymal Progenitor Cells in Lipedema: Distribution, Frequency, and Potentials

Principal Investigator: Bruno Péault, PhD
University of California at Los Angeles (UCLA)
Los Angeles, CA

Co-Principal Investigator: Ayelet Dar, PhD
University of Southern California
Los Angeles, CA

Summary

This project aims to characterize, qualitatively and quantitatively, the stem/progenitor cells present in the diseased tissues of Lipedema patients. Like all tissues, adipose (fat) contains stem cells involved in tissue turnover, healing, and scarring. The profound cellular abnormalities that characterize Lipedema, such as fat cell overgrowth and tissue fibrosis (uncontrolled scarring), suggest these stem cells are not functioning normally. Therefore, stem cell dysregulation might cause or amplify Lipedema. Techniques of cellular and molecular biology will be used to quantify and functionally characterize subsets of stem cells present in different Lipedema fat depots, at different stages of the evolution of the disease.

Background

Lipedema is characterized by severe cellular abnormalities in the subcutaneous fat of patients: fibrosis (invasion by inert, fibrous tissue constituted of cells named fibroblasts that produce collagen and other proteins in excess), fat cell increase, and possibly other flaws affecting, for instance, blood vessels. The origin of these malformations is unknown. Besides, it is well established that normal adipose (fat) contains “mesenchymal stem cells” that can contribute to the regeneration of diverse cellular structures, including fat itself, but also blood vessels and other tissues. This project aims to determine, for the first time, whether mesenchymal stem cells and subsets thereof are dysregulated in Lipedema, and hence responsible for the observed cell anomalies. Such dysregulations might affect the number of these stem cells, or/and the potential thereof to produce fat cells, fibroblasts, or other cell types.

Methodology

The research will be performed at the University of California (UCLA and USC), in close collaboration with Johns Hopkins University. Expert local practitioners (Beverly Hills) who specialize in Lipedema diagnosis and treatment will provide patient tissue samples following surgery or liposuction. Lipedema tissue samples from different anatomic locations and disease stages will be analyzed. Samples from non-Lipedema patients undergoing cosmetic liposuction will be used as controls.

• Immunohistochemistry will allow detecting under the microscope molecules expressed by subsets of mesenchymal stem cells. This technique will be used to determine the relative number and anatomic localization of these cells in Lipedema tissues.

• Viable mesenchymal stem cell subsets will be then purified from tissue samples by flow cytometry (a technique allowing the selection of cells of a given type according to the presence of particular molecules at their surface) and placed in culture. Using relevant culture conditions, the functional properties of the stem cells present in Lipedema tissues will be determined (proliferation, migration, ability to differentiate into fibroblasts and adipocytes).

• Finally, sorted stem cells will be analyzed by RNA sequencing. This allows identifying all proteins expressed in a given cell or cell population, following thorough bioinformatic analysis.

Altogether, these different sets of data will be combined and used to determine how mesenchymal stem cells present in Lipedema tissues, in different anatomic locations and at different stages of the disease, differ, anatomically, quantitatively, and functionally, with respect to counterpart cells encountered in normal subcutaneous fat. In particular, the subsets of mesenchymal stem cells specialized in the generation of adipocytes (fat storing cells) and myofibroblasts (at the origin of fibrosis) that have been recently discovered will be scrutinized

Expected outcomes

The hypothesis that founds this project is that the mesenchymal stem cells normally present in human adipose tissue, where they are natively associated with blood vessels as perivascular cells, are dysregulated in Lipedema. Accordingly, and considering that fibrosis is prominent in Lipedema adipose tissue, we expect that the frequency and potential of fibrogenic cells (the stem cells that produce myofibroblasts, responsible for fibrosis) are higher in Lipedema tissues. We expect that the same applies to adipogenic stem cells, which are responsible for fat cell (aka adipocyte) generation.

Practical implementations of results

The primary goal of this research is to get insight into the etiology (cause) of Lipedema, which is currently unknown. If data will support the overarching hypothesis, characterization of mesenchymal stem cell subsets in patients’ diseased tissues may be used eventually for Lipedema diagnosis and follow-up. Ultimately, therapeutic interventions targeting abnormal or dysfunctional mesenchymal stem cell subsets (antibodies, non-coding RNAs…) should allow controlling these cell populations, restoring normal stem cell function, and slowing down or blocking Lipedema development.

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