Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients

Jean Farup; Jesper Just; Frank de Paoli; Lin Lin; Jonas Brorson Jensen; Tine Billeskov; Ines Sanchez Roman; Cagla Cömert; Andreas Buch Møller; Luca Madaro; Elena Groppa; Rikard Göran Fred; Ulla Kampmann; Lars C Gormsen; Steen B Pedersen; Peter Bross; Tinna Stevnsner; Nikolaj Eldrup; Tune H Pers; Fabio M V Rossi; Pier Lorenzo Puri; Niels Jessen

doi:10.1016/j.cmet.2021.10.001

Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients

Jean Farup^*, Jesper Just, Frank de Paoli, Lin Lin, Jonas Brorson Jensen, Tine Billeskov, Ines Sanchez Roman, Cagla Cömert, Andreas Buch Møller, Luca Madaro, Elena Groppa, Rikard Göran Fred, Ulla Kampmann, Lars C Gormsen, Steen B Pedersen, Peter Bross, Tinna Stevnsner, Nikolaj Eldrup, Tune H Pers, Fabio M V RossiPier Lorenzo Puri, Niels Jessen^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

63 Citations (Scopus)

Abstract

Type 2 diabetes mellitus (T2DM) is associated with impaired skeletal muscle function and degeneration of the skeletal muscles. However, the mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscle of T2DM patients exhibit degenerative remodeling of the extracellular matrix that is associated with a selective increase of a subpopulation of fibro-adipogenic progenitors (FAPs) marked by expression of THY1 (CD90)-the FAPCD90+. We identify platelet-derived growth factor (PDGF) as a key FAP regulator, as it promotes proliferation and collagen production at the expense of adipogenesis. FAPsCD90+ display a PDGF-mimetic phenotype, with high proliferative activity, clonogenicity, and production of extracellular matrix. FAPCD90+ proliferation was reduced by in vitro treatment with metformin. Furthermore, metformin treatment reduced FAP content in T2DM patients. These data identify a PDGF-driven conversion of a subpopulation of FAPs as a key event in the fibrosis development in T2DM muscle.

Original language	English
Journal	Cell Metabolism
Volume	33
Issue	11
Pages (from-to)	2201-2214.e10
Number of pages	25
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2021.10.001
Publication status	Published - Nov 2021

Keywords

adipocytes
extracellular matrix
fatty degeneration
fibro-adipogenic progenitors
fibroblast
fibrosis
mesenchymal stem cells
skeletal muscle
type 2 diabetes
ACTIVATION
STEM-CELLS
RESIDENT
POLYADENYLATION
DECREASES
STAIN-FREE TECHNOLOGY
METABOLISM
INSULIN-RESISTANCE
PDGFR-ALPHA
FIBRO/ADIPOGENIC PROGENITORS

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10.1016/j.cmet.2021.10.001

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9165662/pdf/nihms-1803774.pdf

Cite this

Farup, J., Just, J., de Paoli, F., Lin, L., Jensen, J. B., Billeskov, T., Roman, I. S., Cömert, C., Møller, A. B., Madaro, L., Groppa, E., Fred, R. G., Kampmann, U., Gormsen, L. C., Pedersen, S. B., Bross, P., Stevnsner, T., Eldrup, N., Pers, T. H., ... Jessen, N. (2021). Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients. Cell Metabolism, 33(11), 2201-2214.e10. https://doi.org/10.1016/j.cmet.2021.10.001

@article{471637dfbfde44f98d023069f903a09d,

title = "Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients",

abstract = "Type 2 diabetes mellitus (T2DM) is associated with impaired skeletal muscle function and degeneration of the skeletal muscles. However, the mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscle of T2DM patients exhibit degenerative remodeling of the extracellular matrix that is associated with a selective increase of a subpopulation of fibro-adipogenic progenitors (FAPs) marked by expression of THY1 (CD90)-the FAPCD90+. We identify platelet-derived growth factor (PDGF) as a key FAP regulator, as it promotes proliferation and collagen production at the expense of adipogenesis. FAPsCD90+ display a PDGF-mimetic phenotype, with high proliferative activity, clonogenicity, and production of extracellular matrix. FAPCD90+ proliferation was reduced by in vitro treatment with metformin. Furthermore, metformin treatment reduced FAP content in T2DM patients. These data identify a PDGF-driven conversion of a subpopulation of FAPs as a key event in the fibrosis development in T2DM muscle.",

keywords = "adipocytes, extracellular matrix, fatty degeneration, fibro-adipogenic progenitors, fibroblast, fibrosis, mesenchymal stem cells, skeletal muscle, type 2 diabetes, ACTIVATION, STEM-CELLS, RESIDENT, POLYADENYLATION, DECREASES, STAIN-FREE TECHNOLOGY, METABOLISM, INSULIN-RESISTANCE, PDGFR-ALPHA, FIBRO/ADIPOGENIC PROGENITORS",

author = "Jean Farup and Jesper Just and {de Paoli}, Frank and Lin Lin and Jensen, {Jonas Brorson} and Tine Billeskov and Roman, {Ines Sanchez} and Cagla C{\"o}mert and M{\o}ller, {Andreas Buch} and Luca Madaro and Elena Groppa and Fred, {Rikard G{\"o}ran} and Ulla Kampmann and Gormsen, {Lars C} and Pedersen, {Steen B} and Peter Bross and Tinna Stevnsner and Nikolaj Eldrup and Pers, {Tune H} and Rossi, {Fabio M V} and Puri, {Pier Lorenzo} and Niels Jessen",

year = "2021",

month = nov,

doi = "10.1016/j.cmet.2021.10.001",

language = "English",

volume = "33",

pages = "2201--2214.e10",

journal = "Cell Metabolism",

issn = "1550-4131",

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number = "11",

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Farup, J , Just, J , de Paoli, F , Lin, L, Jensen, JB, Billeskov, T, Roman, IS, Cömert, C, Møller, AB, Madaro, L, Groppa, E, Fred, RG, Kampmann, U , Gormsen, LC , Pedersen, SB , Bross, P , Stevnsner, T, Eldrup, N, Pers, TH, Rossi, FMV, Puri, PL & Jessen, N 2021, 'Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients', Cell Metabolism, vol. 33, no. 11, pp. 2201-2214.e10. https://doi.org/10.1016/j.cmet.2021.10.001

Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients. / Farup, Jean ; Just, Jesper ; de Paoli, Frank et al.
In: Cell Metabolism, Vol. 33, No. 11, 11.2021, p. 2201-2214.e10.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients

AU - Farup, Jean

AU - Just, Jesper

AU - de Paoli, Frank

AU - Lin, Lin

AU - Jensen, Jonas Brorson

AU - Billeskov, Tine

AU - Roman, Ines Sanchez

AU - Cömert, Cagla

AU - Møller, Andreas Buch

AU - Madaro, Luca

AU - Groppa, Elena

AU - Fred, Rikard Göran

AU - Kampmann, Ulla

AU - Gormsen, Lars C

AU - Pedersen, Steen B

AU - Bross, Peter

AU - Stevnsner, Tinna

AU - Eldrup, Nikolaj

AU - Pers, Tune H

AU - Rossi, Fabio M V

AU - Puri, Pier Lorenzo

AU - Jessen, Niels

PY - 2021/11

Y1 - 2021/11

N2 - Type 2 diabetes mellitus (T2DM) is associated with impaired skeletal muscle function and degeneration of the skeletal muscles. However, the mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscle of T2DM patients exhibit degenerative remodeling of the extracellular matrix that is associated with a selective increase of a subpopulation of fibro-adipogenic progenitors (FAPs) marked by expression of THY1 (CD90)-the FAPCD90+. We identify platelet-derived growth factor (PDGF) as a key FAP regulator, as it promotes proliferation and collagen production at the expense of adipogenesis. FAPsCD90+ display a PDGF-mimetic phenotype, with high proliferative activity, clonogenicity, and production of extracellular matrix. FAPCD90+ proliferation was reduced by in vitro treatment with metformin. Furthermore, metformin treatment reduced FAP content in T2DM patients. These data identify a PDGF-driven conversion of a subpopulation of FAPs as a key event in the fibrosis development in T2DM muscle.

AB - Type 2 diabetes mellitus (T2DM) is associated with impaired skeletal muscle function and degeneration of the skeletal muscles. However, the mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscle of T2DM patients exhibit degenerative remodeling of the extracellular matrix that is associated with a selective increase of a subpopulation of fibro-adipogenic progenitors (FAPs) marked by expression of THY1 (CD90)-the FAPCD90+. We identify platelet-derived growth factor (PDGF) as a key FAP regulator, as it promotes proliferation and collagen production at the expense of adipogenesis. FAPsCD90+ display a PDGF-mimetic phenotype, with high proliferative activity, clonogenicity, and production of extracellular matrix. FAPCD90+ proliferation was reduced by in vitro treatment with metformin. Furthermore, metformin treatment reduced FAP content in T2DM patients. These data identify a PDGF-driven conversion of a subpopulation of FAPs as a key event in the fibrosis development in T2DM muscle.

KW - adipocytes

KW - extracellular matrix

KW - fatty degeneration

KW - fibro-adipogenic progenitors

KW - fibroblast

KW - fibrosis

KW - mesenchymal stem cells

KW - skeletal muscle

KW - type 2 diabetes

KW - ACTIVATION

KW - STEM-CELLS

KW - RESIDENT

KW - POLYADENYLATION

KW - DECREASES

KW - STAIN-FREE TECHNOLOGY

KW - METABOLISM

KW - INSULIN-RESISTANCE

KW - PDGFR-ALPHA

KW - FIBRO/ADIPOGENIC PROGENITORS

U2 - 10.1016/j.cmet.2021.10.001

DO - 10.1016/j.cmet.2021.10.001

M3 - Journal article

C2 - 34678202

SN - 1550-4131

VL - 33

SP - 2201-2214.e10

JO - Cell Metabolism

JF - Cell Metabolism

IS - 11

ER -

Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients

Abstract

Keywords

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