title: Aging disrupts cell subpopulation dynamics and diminishes the function of mesenchymal stem cells.
abstract: Advanced age is associated with an increased risk of vascular morbidity, attributable in part to impairments in new blood vessel formation. Mesenchymal stem cells (MSCs) have previously been shown to play an important role in neovascularization and deficiencies in these cells have been described in aged patients. Here we utilize single cell transcriptional analysis to determine the effect of aging on MSC population dynamics. We identify an age-related depletion of a subpopulation of MSCs characterized by a pro-vascular transcriptional profile. Supporting this finding, we demonstrate that aged MSCs are also significantly compromised in their ability to support vascular network formation in vitro and in vivo. Finally, aged MSCs are unable to rescue age-associated impairments in cutaneous wound healing. Taken together, these data suggest that age-related changes in MSC population dynamics result in impaired therapeutic potential of aged progenitor cells. These findings have critical implications for therapeutic cell source decisions (autologous versus allogeneic) and indicate the necessity of strategies to improve functionality of aged MSCs.
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine; Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Dominik
authors.initials: D
authors.lastname: Duscher
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine; Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rennert
authors.affiliation: 1] Hagey Laboratory for Pediatric Regenerative Medicine; Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA [2] Program in Biomedical Informatics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Januszyk
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine; Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Ersilia
authors.initials: E
authors.lastname: Anghel
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine; Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Zeshaan N
authors.initials: ZN
authors.lastname: Maan
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine; Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Whittam
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine; Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Marcelina G
authors.initials: MG
authors.lastname: Perez
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine; Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Revanth
authors.initials: R
authors.lastname: Kosaraju
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine; Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hu
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine; Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Walmsley
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine; Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Atashroo
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine; Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Sacha
authors.initials: S
authors.lastname: Khong
authors.affiliation: 1] Program in Biomedical Informatics, Stanford University School of Medicine, Stanford, CA, USA [2] Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
authors.affiliation: Hagey Laboratory for Pediatric Regenerative Medicine; Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Gurtner
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000375:Aging; D000818:Animals; D002478:Cells, Cultured; D016000:Cluster Analysis; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D053263:Gene Regulatory Networks; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D059467:Transcriptome; D014404:Tubulin / Q000378:metabolism; D014945:Wound Healing
chemical_list: D016207:Cytokines; D014404:Tubulin