Identification Of A Mesenchymal Progenitor Cell Hierarchy In Adipose Tissue

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dc.contributor.advisorPatrick . Seale
dc.contributor.advisorMitchell A. Lazar
dc.contributor.authorSakers, Alexander Paul
dc.date2023-05-17T23:28:55.000
dc.date.accessioned2023-05-22T17:45:22Z
dc.date.available2001-01-01T00:00:00Z
dc.date.copyright2020-02-07T20:19:00-08:00
dc.date.issued2019-01-01
dc.date.submitted2020-02-07T14:06:02-08:00
dc.description.abstractAdipose tissue plays a critical role in defending against metabolic disease by sequestering excess calories and preventing their harmful deposition in ectopic locations. Healthy expansion of adipose occurs via hyperplastic growth, the differentiation of adipocyte progenitor cells (APCs) into new fat cells. The capacity for hyperplastic expansion depends on the fundamental properties of APCs. Prior studies of APCs used narrow identification methods and did not fully characterize the identity and nature of APCs. We used single-cell RNA sequencing to identify distinct types of progenitor cells in murine and human adipose tissue. Functional assessments of these cell types in vitro and in vivo define a mesenchymal cell hierarchy involved in adipocyte formation. We identified 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+ cells represent a distinct adipogenic population in murine subcutaneous adipose that shares many properties with ICAM1+ preadipocytes. Computational cell trajectory analyses and in vivo 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–b signaling to maintain their progenitor identity. Obesity and insulin resistance lead to a depletion of DPP4+ progenitors and a reduction in the adipogenic differentiation competency of APCs 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. The DPP4+ progenitor cells are localized in a previously uncharacterized fibrous niche which surrounds adipose depots, which we term the reticular interstitium. Overall, our studies define the developmental hierarchy of adipose progenitors, describe a new anatomic niche, and lay the groundwork for future therapies targeting one or more of these APC populations.
dc.description.degreeDoctor of Philosophy (PhD)
dc.format.extent222 p.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://repository.upenn.edu/handle/20.500.14332/30598
dc.languageen
dc.legacy.articleid5347
dc.legacy.fulltexturlhttps://repository.upenn.edu/cgi/viewcontent.cgi?article=5347&context=edissertations&unstamped=1
dc.provenanceReceived from ProQuest
dc.rightsAlexander Paul Sakers
dc.source.issue3561
dc.source.journalPublicly Accessible Penn Dissertations
dc.source.statuspublished
dc.subject.otherAdipose development
dc.subject.otherAdipose tissue
dc.subject.otherDPP4
dc.subject.otherFat tissue
dc.subject.otherICAM1
dc.subject.otherSingle cell biology
dc.subject.otherCell Biology
dc.subject.otherDevelopmental Biology
dc.titleIdentification Of A Mesenchymal Progenitor Cell Hierarchy In Adipose Tissue
dc.typeDissertation/Thesis
digcom.contributor.authorSakers, Alexander Paul
digcom.date.embargo2001-01-01T00:00:00-08:00
digcom.identifieredissertations/3561
digcom.identifier.contextkey16484256
digcom.identifier.submissionpathedissertations/3561
digcom.typedissertation
dspace.entity.typePublication
upenn.graduate.groupCell & Molecular Biology
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