Secretome of adipose-derived mesenchymal stem cells promotes skeletal muscle regeneration through synergistic action of extracellular vesicle cargo and soluble proteins

Robert Mitchell, Ben Mellows, Jonathan Sheard, Manuela Antonioli, Oliver Kretz, David Chambers, Marie Theres Zeuner, James E. Tomkins, Bernd Denecke, Luca Musante, Barbara Joch, Florence Debacq-Chainiaux, Harry Holthofer, Steve Ray, Tobias B. Huber, Joern Dengjel, Paolo De Coppi, Darius Widera, Ketan Patel

Research output: Contribution to journalArticle

Abstract

Background : The mechanisms underpinning the regenerative capabilities of mesenchymal stem cells (MSC) were originally thought to reside in their ability to recognise damaged tissue and to differentiate into specific cell types that would replace defective cells. However, recent work has shown that molecules produced by MSCs (secretome), particularly those packaged in extracellular vesicles (EVs), rather than the cells themselves are responsible for tissue repair. Methods: Here we have produced a secretome from adipose-derived mesenchymal stem cells (ADSC) that is free of exogenous molecules by incubation within a saline solution. Various in vitro models were used to evaluate the effects of the secretome on cellular processes that promote tissue regeneration. A cardiotoxin-induced skeletal muscle injury model was used to test the regenerative effects of the whole secretome or isolated extracellular vesicle fraction in vivo. This was followed by bioinformatic analysis of the components of the protein and miRNA content of the secretome and finally compared to a secretome generated from a secondary stem cell source. Results: Here we have demonstrated that the secretome from adipose-derived mesenchymal stem cells shows robust effects on cellular processes that promote tissue regeneration. Furthermore, we show that the whole ADSC secretome is capable of enhancing the rate of skeletal muscle regeneration following acute damage. We assessed the efficacy of the total secretome compared with the extracellular vesicle fraction on a number of assays that inform on tissue regeneration and demonstrate that both fractions affect different aspects of the process in vitro and in vivo. Our in vitro, in vivo, and bioinformatic results show that factors that promote regeneration are distributed both within extracellular vesicles and the soluble fraction of the secretome. Conclusions: Taken together, our study implies that extracellular vesicles and soluble molecules within ADSC secretome act in a synergistic manner to promote muscle generation.

Original languageEnglish
Article number116
Number of pages19
JournalStem Cell Research and Therapy
Volume10
Issue number1
DOIs
Publication statusPublished - 5 Apr 2019

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Stem cells
Mesenchymal Stromal Cells
Muscle
Regeneration
Skeletal Muscle
Tissue regeneration
Proteins
Computational Biology
Bioinformatics
Molecules
Cardiotoxins
Tissue
MicroRNAs
Sodium Chloride
Stem Cells
Extracellular Vesicles
Assays
Repair
Muscles
Wounds and Injuries

Keywords

  • Adipose-derived mesenchymal stem cell
  • Extracellular vesicles
  • Inflammation
  • microRNA
  • Muscle
  • Proteomic
  • Regeneration
  • Secretome

Cite this

Mitchell, Robert ; Mellows, Ben ; Sheard, Jonathan ; Antonioli, Manuela ; Kretz, Oliver ; Chambers, David ; Zeuner, Marie Theres ; Tomkins, James E. ; Denecke, Bernd ; Musante, Luca ; Joch, Barbara ; Debacq-Chainiaux, Florence ; Holthofer, Harry ; Ray, Steve ; Huber, Tobias B. ; Dengjel, Joern ; De Coppi, Paolo ; Widera, Darius ; Patel, Ketan. / Secretome of adipose-derived mesenchymal stem cells promotes skeletal muscle regeneration through synergistic action of extracellular vesicle cargo and soluble proteins. In: Stem Cell Research and Therapy. 2019 ; Vol. 10, No. 1.
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Mitchell, R, Mellows, B, Sheard, J, Antonioli, M, Kretz, O, Chambers, D, Zeuner, MT, Tomkins, JE, Denecke, B, Musante, L, Joch, B, Debacq-Chainiaux, F, Holthofer, H, Ray, S, Huber, TB, Dengjel, J, De Coppi, P, Widera, D & Patel, K 2019, 'Secretome of adipose-derived mesenchymal stem cells promotes skeletal muscle regeneration through synergistic action of extracellular vesicle cargo and soluble proteins', Stem Cell Research and Therapy, vol. 10, no. 1, 116. https://doi.org/10.1186/s13287-019-1213-1

Secretome of adipose-derived mesenchymal stem cells promotes skeletal muscle regeneration through synergistic action of extracellular vesicle cargo and soluble proteins. / Mitchell, Robert; Mellows, Ben; Sheard, Jonathan; Antonioli, Manuela; Kretz, Oliver; Chambers, David; Zeuner, Marie Theres; Tomkins, James E.; Denecke, Bernd; Musante, Luca; Joch, Barbara; Debacq-Chainiaux, Florence; Holthofer, Harry; Ray, Steve; Huber, Tobias B.; Dengjel, Joern; De Coppi, Paolo; Widera, Darius; Patel, Ketan.

In: Stem Cell Research and Therapy, Vol. 10, No. 1, 116, 05.04.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Secretome of adipose-derived mesenchymal stem cells promotes skeletal muscle regeneration through synergistic action of extracellular vesicle cargo and soluble proteins

AU - Mitchell, Robert

AU - Mellows, Ben

AU - Sheard, Jonathan

AU - Antonioli, Manuela

AU - Kretz, Oliver

AU - Chambers, David

AU - Zeuner, Marie Theres

AU - Tomkins, James E.

AU - Denecke, Bernd

AU - Musante, Luca

AU - Joch, Barbara

AU - Debacq-Chainiaux, Florence

AU - Holthofer, Harry

AU - Ray, Steve

AU - Huber, Tobias B.

AU - Dengjel, Joern

AU - De Coppi, Paolo

AU - Widera, Darius

AU - Patel, Ketan

PY - 2019/4/5

Y1 - 2019/4/5

N2 - Background : The mechanisms underpinning the regenerative capabilities of mesenchymal stem cells (MSC) were originally thought to reside in their ability to recognise damaged tissue and to differentiate into specific cell types that would replace defective cells. However, recent work has shown that molecules produced by MSCs (secretome), particularly those packaged in extracellular vesicles (EVs), rather than the cells themselves are responsible for tissue repair. Methods: Here we have produced a secretome from adipose-derived mesenchymal stem cells (ADSC) that is free of exogenous molecules by incubation within a saline solution. Various in vitro models were used to evaluate the effects of the secretome on cellular processes that promote tissue regeneration. A cardiotoxin-induced skeletal muscle injury model was used to test the regenerative effects of the whole secretome or isolated extracellular vesicle fraction in vivo. This was followed by bioinformatic analysis of the components of the protein and miRNA content of the secretome and finally compared to a secretome generated from a secondary stem cell source. Results: Here we have demonstrated that the secretome from adipose-derived mesenchymal stem cells shows robust effects on cellular processes that promote tissue regeneration. Furthermore, we show that the whole ADSC secretome is capable of enhancing the rate of skeletal muscle regeneration following acute damage. We assessed the efficacy of the total secretome compared with the extracellular vesicle fraction on a number of assays that inform on tissue regeneration and demonstrate that both fractions affect different aspects of the process in vitro and in vivo. Our in vitro, in vivo, and bioinformatic results show that factors that promote regeneration are distributed both within extracellular vesicles and the soluble fraction of the secretome. Conclusions: Taken together, our study implies that extracellular vesicles and soluble molecules within ADSC secretome act in a synergistic manner to promote muscle generation.

AB - Background : The mechanisms underpinning the regenerative capabilities of mesenchymal stem cells (MSC) were originally thought to reside in their ability to recognise damaged tissue and to differentiate into specific cell types that would replace defective cells. However, recent work has shown that molecules produced by MSCs (secretome), particularly those packaged in extracellular vesicles (EVs), rather than the cells themselves are responsible for tissue repair. Methods: Here we have produced a secretome from adipose-derived mesenchymal stem cells (ADSC) that is free of exogenous molecules by incubation within a saline solution. Various in vitro models were used to evaluate the effects of the secretome on cellular processes that promote tissue regeneration. A cardiotoxin-induced skeletal muscle injury model was used to test the regenerative effects of the whole secretome or isolated extracellular vesicle fraction in vivo. This was followed by bioinformatic analysis of the components of the protein and miRNA content of the secretome and finally compared to a secretome generated from a secondary stem cell source. Results: Here we have demonstrated that the secretome from adipose-derived mesenchymal stem cells shows robust effects on cellular processes that promote tissue regeneration. Furthermore, we show that the whole ADSC secretome is capable of enhancing the rate of skeletal muscle regeneration following acute damage. We assessed the efficacy of the total secretome compared with the extracellular vesicle fraction on a number of assays that inform on tissue regeneration and demonstrate that both fractions affect different aspects of the process in vitro and in vivo. Our in vitro, in vivo, and bioinformatic results show that factors that promote regeneration are distributed both within extracellular vesicles and the soluble fraction of the secretome. Conclusions: Taken together, our study implies that extracellular vesicles and soluble molecules within ADSC secretome act in a synergistic manner to promote muscle generation.

KW - Adipose-derived mesenchymal stem cell

KW - Extracellular vesicles

KW - Inflammation

KW - microRNA

KW - Muscle

KW - Proteomic

KW - Regeneration

KW - Secretome

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U2 - 10.1186/s13287-019-1213-1

DO - 10.1186/s13287-019-1213-1

M3 - Article

VL - 10

JO - Stem Cell Research and Therapy

JF - Stem Cell Research and Therapy

SN - 1757-6512

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ER -