Ultrafiltration and Injection of Islet Regenerative Stimuli Secreted by Pancreatic Mesenchymal Stromal Cells.


Journal

Stem cells and development
ISSN: 1557-8534
Titre abrégé: Stem Cells Dev
Pays: United States
ID NLM: 101197107

Informations de publication

Date de publication:
03 2021
Historique:
pubmed: 7 1 2021
medline: 15 12 2021
entrez: 6 1 2021
Statut: ppublish

Résumé

The secretome of mesenchymal stromal cells (MSCs) is enriched for biotherapeutic effectors contained within and independent of extracellular vesicles (EVs) that may support tissue regeneration as an injectable agent. We have demonstrated that the intrapancreatic injection of concentrated conditioned media (CM) produced by bone marrow MSC supports islet regeneration and restored glycemic control in hyperglycemic mice, ultimately providing a platform to elucidate components of the MSC secretome. Herein, we extend these findings using human pancreas-derived MSC (Panc-MSC) as "biofactories" to enrich for tissue regenerative stimuli housed within distinct compartments of the secretome. Specifically, we utilized 100 kDa ultrafiltration as a simple method to debulk protein mass and to enrich for EVs while concentrating the MSC secretome into an injectable volume for preclinical assessments in murine models of blood vessel and islet regeneration. EV enrichment (EV+) was validated using nanoscale flow cytometry and atomic force microscopy, in addition to the detection of classical EV markers CD9, CD81, and CD63 using label-free mass spectrometry. EV+ CM was predominately enriched with mediators of wound healing and epithelial-to-mesenchymal transition that supported functional regeneration in mesenchymal and nonmesenchymal tissues. For example, EV+ CM supported human microvascular endothelial cell tubule formation in vitro and enhanced the recovery of blood perfusion following intramuscular injection in nonobese diabetic/severe combined immunodeficiency mice with unilateral hind limb ischemia. Furthermore, EV+ CM increased islet number and β cell mass, elevated circulating insulin, and improved glycemic control following intrapancreatic injection in streptozotocin-treated mice. Collectively, this study provides foundational evidence that Panc-MSC, readily propagated from the subculture of human islets, may be utilized for regenerative medicine applications.

Identifiants

pubmed: 33403929
doi: 10.1089/scd.2020.0206
pmc: PMC10331161
doi:

Substances chimiques

Biological Factors 0
Culture Media, Conditioned 0
Streptozocin 5W494URQ81

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

247-264

Subventions

Organisme : NIDDK NIH HHS
ID : U24 DK098085
Pays : United States

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Auteurs

Tyler T Cooper (TT)

Department of Physiology and Pharmacology, Western University, London, Canada.
Molecular Medicine Research Laboratories, Robarts Research Institute, London, Canada.
Don Rix Protein Identification Facility, Department of Biochemistry and Western University, London, Canada.

Stephen E Sherman (SE)

Department of Physiology and Pharmacology, Western University, London, Canada.
Molecular Medicine Research Laboratories, Robarts Research Institute, London, Canada.

Gillian I Bell (GI)

Molecular Medicine Research Laboratories, Robarts Research Institute, London, Canada.

Thamara Dayarathna (T)

Molecular Medicine Research Laboratories, Robarts Research Institute, London, Canada.

Danielle M McRae (DM)

Department of Chemistry, Western University, London, Canada.

Jun Ma (J)

Molecular Medicine Research Laboratories, Robarts Research Institute, London, Canada.
Don Rix Protein Identification Facility, Department of Biochemistry and Western University, London, Canada.

François Lagugné-Labarthet (F)

Department of Chemistry, Western University, London, Canada.

Stephen H Pasternak (SH)

Molecular Medicine Research Laboratories, Robarts Research Institute, London, Canada.

Gilles A Lajoie (GA)

Don Rix Protein Identification Facility, Department of Biochemistry and Western University, London, Canada.

David A Hess (DA)

Department of Physiology and Pharmacology, Western University, London, Canada.
Molecular Medicine Research Laboratories, Robarts Research Institute, London, Canada.

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