Comparative single-cell lineage tracing identifies distinct adipocyte precursor dynamics in skin and inguinal fat

Guillermo C. Rivera-Gonzalez, Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: guillermo@capybio.com.
Emily G. Butka, Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Carolynn E. Gonzalez, Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Rachel L. Mintz, Department of Biomedical Engineering, Washington University in St. Louis, 6201 Forsyth Blvd, St. Louis, MO 63105, USA.
Sarah S. Kleb, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA.
Violet Josephson, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA.
Wenjun Kong, Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Kunal Jindal, Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Kenji Kamimoto, Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Brett A. Shook, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA; Department of Dermatology, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA.
Matthew S. Rodeheffer, Department of Comparative Medicine, Yale University, New Haven, CT, USA.
Samantha A. Morris, Division of Gastroenterology, Hepatology and Endoscopy, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: samorris2@bwh.harvard.edu.

Document Type

Journal Article

Publication Date

8-7-2025

Journal

Cell stem cell

Volume

32

Issue

8

DOI

10.1016/j.stem.2025.07.004

Keywords

Sox9; adipocyte precursors; adipogenesis; cell proliferation; single-cell lineage tracing; skin adipose hierarchy

Abstract

White adipose tissue supports essential physiological functions through adipocyte precursor cells (APCs), comprising progenitors and preadipocytes, which generate mature adipocytes during depot expansion. Using single-cell RNA sequencing-based lineage tracing, we characterize APCs in skin adipose tissue-a depot uniquely capable of rapid adipogenesis compared with other sites, such as inguinal adipose. We identify a previously uncharacterized population of immature preadipocytes and reveal distinct differentiation potentials among APCs. Contrary to traditional stepwise differentiation models, progenitors predominantly generate committed preadipocytes, whereas preexisting preadipocytes accumulate in immature states with divergent potential. Leveraging this refined APC hierarchy, we uncover Sox9 as a crucial regulator of progenitor proliferation and adipogenic differentiation. Cross-depot transplantation further demonstrates how intrinsic and extrinsic factors differentially regulate skin progenitor behavior, highlighting distinct adipogenic dynamics between skin and inguinal depots. Together, these insights redefine the cellular hierarchy and molecular mechanisms underpinning rapid adipogenesis in skin adipose tissue.

Department

Biochemistry and Molecular Medicine

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