Single-cell lineage tracing reveals hierarchy and mechanism of adipocyte precursor maturation

White adipose tissue is crucial in various physiological processes. In response to high caloric intake, adipose tissue may expand by generating new adipocytes. Adipocyte precursor cells (progenitors and preadipocytes) are essential for generating mature adipocytes, and single-cell RNA sequencing provides new means to identify these populations. Here, we characterized adipocyte precursor populations in the skin, an adipose depot with rapid and robust generation of mature adipocytes. We identified a new population of immature preadipocytes, revealed a biased differentiation potential of progenitor cells, and identified Sox9 as a critical factor in driving progenitors toward adipose commitment, the first known mechanism of progenitor differentiation. These findings shed light on the specific dynamics and molecular mechanisms underlying rapid adipogenesis in the skin.

[1]  Samantha A. Morris,et al.  Multiomic single-cell lineage tracing to dissect fate-specific gene regulatory programs , 2022, bioRxiv.

[2]  Y. Lee,et al.  Distinct properties of adipose stem cell subpopulations determine fat depot-specific characteristics. , 2022, Cell metabolism.

[3]  Q. Phan,et al.  Parallel single cell multi-omics analysis of neonatal skin reveals transitional fibroblast states that restricts differentiation into distinct fates. , 2021, The Journal of investigative dermatology.

[4]  Bernard T. Lee,et al.  A single-cell atlas of human and mouse white adipose tissue , 2021, Nature.

[5]  P. Seale,et al.  Dpp4+ interstitial progenitor cells contribute to basal and high fat diet-induced adipogenesis , 2021, Molecular metabolism.

[6]  R. Bourgon,et al.  Cross-tissue organization of the fibroblast lineage , 2021, Nature.

[7]  S. Mandrup,et al.  Plasticity of Epididymal Adipose Tissue in Response to Diet-Induced Obesity at Single-Nucleus Resolution. , 2020, Cell metabolism.

[8]  Samantha A. Morris,et al.  Next-Generation Lineage Tracing and Fate Mapping to Interrogate Development. , 2020, Developmental cell.

[9]  Yasin Kaymaz,et al.  Evaluating single-cell cluster stability using the Jaccard similarity index , 2020, bioRxiv.

[10]  Damon A. Clark,et al.  Dermal Adipocyte Lipolysis and Myofibroblast Conversion Are Required for Efficient Skin Repair. , 2020, Cell stem cell.

[11]  Samantha A. Morris,et al.  Capybara: A computational tool to measure cell identity and fate transitions , 2020, bioRxiv.

[12]  Samantha A. Morris,et al.  CellTagging: combinatorial indexing to simultaneously map lineage and identity at single-cell resolution , 2020, Nature Protocols.

[13]  S. Dimmeler,et al.  Parallel Lineage-Tracing Studies Establish Fibroblasts as the Prevailing In Vivo Adipocyte Progenitor. , 2020, Cell reports.

[14]  P. Scherer,et al.  Dermal adipose tissue has high plasticity and undergoes reversible dedifferentiation in mice. , 2019, The Journal of clinical investigation.

[15]  S. Orkin,et al.  An Engineered CRISPR-Cas9 Mouse Line for Simultaneous Readout of Lineage Histories and Gene Expression Profiles in Single Cells , 2019, Cell.

[16]  Rana K. Gupta,et al.  Contribution of adipogenesis to healthy adipose tissue expansion in obesity. , 2019, The Journal of clinical investigation.

[17]  C. Kahn,et al.  Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. , 2019, The Journal of clinical investigation.

[18]  R. Sandberg,et al.  The molecular anatomy of mouse skin during hair growth and rest , 2019, bioRxiv.

[19]  Samantha A. Morris,et al.  CellTag Indexing: genetic barcode-based sample multiplexing for single-cell genomics , 2019, Genome Biology.

[20]  Ivona Percec,et al.  Identification of a mesenchymal progenitor cell hierarchy in adipose tissue , 2019, Science.

[21]  Qing Nie,et al.  Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds , 2019, Nature Communications.

[22]  P. Scherer,et al.  Adipogenesis and metabolic health , 2019, Nature Reviews Molecular Cell Biology.

[23]  Damon A. Clark,et al.  Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair , 2018, Science.

[24]  Samantha A. Morris,et al.  Single-cell mapping of lineage and identity in direct reprogramming , 2018, Nature.

[25]  P. Rompolas,et al.  Flexible fate determination ensures robust differentiation in the hair follicle , 2018, Nature Cell Biology.

[26]  H. Sul,et al.  Sox9-Meis1 Inactivation Is Required for Adipogenesis, Advancing Pref-1+ to PDGFRα+ Cells , 2018, Cell reports.

[27]  Mengle Shao,et al.  Identification of functionally distinct fibro-inflammatory and adipogenic stromal subpopulations in visceral adipose tissue of adult mice , 2018, eLife.

[28]  R. Pique-Regi,et al.  Deconstructing Adipogenesis Induced by β3-Adrenergic Receptor Activation with Single-Cell Expression Profiling. , 2018, Cell metabolism.

[29]  Petra C. Schwalie,et al.  A stromal cell population that inhibits adipogenesis in mammalian fat depots , 2018, Nature.

[30]  Bo Shan,et al.  De novo adipocyte differentiation from Pdgfrβ+ preadipocytes protects against pathologic visceral adipose expansion in obesity , 2018, Nature Communications.

[31]  L. Garza,et al.  Adipose and Hair Function: An aPPARent Connection. , 2018, The Journal of investigative dermatology.

[32]  A. Mortazavi,et al.  Regeneration of fat cells from myofibroblasts during wound healing , 2017, Science.

[33]  C. Betsholtz,et al.  Skin Adipocyte Stem Cell Self-Renewal Is Regulated by a PDGFA/AKT-Signaling Axis. , 2016, Cell stem cell.

[34]  Y. Hsu,et al.  Hair follicles’ transit-amplifying cells govern concurrent dermal adipocyte production through Sonic Hedgehog , 2016, Genes & development.

[35]  Ryan Berry,et al.  The Adipose Tissue Microenvironment Regulates Depot-Specific Adipogenesis in Obesity. , 2016, Cell metabolism.

[36]  A. McMahon,et al.  Sox9 Activation Highlights a Cellular Pathway of Renal Repair in the Acutely Injured Mammalian Kidney. , 2015, Cell reports.

[37]  M. Rodeheffer,et al.  Rapid Depot-Specific Activation of Adipocyte Precursor Cells at the Onset of Obesity , 2015, Nature Cell Biology.

[38]  M. Plikus,et al.  Dermal adipocytes protect against invasive Staphylococcus aureus skin infection , 2015, Science.

[39]  J. Graff,et al.  Independent stem cell lineages regulate adipose organogenesis and adipose homeostasis. , 2014, Cell reports.

[40]  M. Blüher,et al.  Adipocyte dysfunction, inflammation and metabolic syndrome , 2014, Reviews in Endocrine and Metabolic Disorders.

[41]  Ryan Berry,et al.  Weighing in on adipocyte precursors. , 2014, Cell metabolism.

[42]  P. Scherer,et al.  Tracking adipogenesis during white adipose tissue development, expansion and regeneration , 2013, Nature Medicine.

[43]  T. Schumacher,et al.  Diverse and heritable lineage imprinting of early haematopoietic progenitors , 2013, Nature.

[44]  Ryan Berry,et al.  Characterization of the adipocyte cellular lineage in vivo , 2013, Nature Cell Biology.

[45]  B. Emanuelli,et al.  Intrinsic Differences in Adipocyte Precursor Cells From Different White Fat Depots , 2012, Diabetes.

[46]  Diti Chatterjee Bhowmick,et al.  Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. , 2012, Cell metabolism.

[47]  D. Chan,et al.  SOX9 Governs Differentiation Stage-Specific Gene Expression in Growth Plate Chondrocytes via Direct Concomitant Transactivation and Repression , 2011, PLoS genetics.

[48]  N. Neff,et al.  NIH Public Access Author Manuscript , 2006 .

[49]  V. Horsley,et al.  Adipocyte Lineage Cells Contribute to the Skin Stem Cell Niche to Drive Hair Cycling , 2011, Cell.

[50]  Chad A. Cowan,et al.  Rapid Cellular Turnover in Adipose Tissue , 2011, PloS one.

[51]  R. Hammer,et al.  White Fat Progenitor Cells Reside in the Adipose Vasculature , 2008, Science.

[52]  J. Friedman,et al.  Identification of White Adipocyte Progenitor Cells In Vivo , 2008, Cell.

[53]  C. Vinson,et al.  Dominant-negative C/EBP disrupts mitotic clonal expansion and differentiation of 3T3-L1 preadipocytes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[54]  M. Olive,et al.  Life without white fat: a transgenic mouse. , 1998, Genes & development.

[55]  Teri A. Crosby,et al.  How to Detect and Handle Outliers , 1993 .