Fibroblasts Derived from Human Pluripotent Stem Cells Activate Angiogenic Responses In Vitro and In Vivo
Open accessAbstract
Human embryonic and induced pluripotent stem cells (hESC/hiPSC) are promising cell sources for the derivation of large numbers of specific cell types for tissue engineering and cell therapy applications. We have describe a directed differentiation protocol that generates fibroblasts from both hESC and hiPSC (EDK/iPDK) that support the repair and regeneration of epithelial tissue in engineered, 3D skin equivalents. In the current study, we analyzed the secretory profiles of EDK and iPDK cells to investigate the production of factors that activate and promote angiogenesis. Analysis of in vitro secretion profiles from EDK and iPDK cells demonstrated the elevated secretion of pro-angiogenic soluble mediators, including VEGF, HGF, IL-8, PDGF-AA, and Ang-1, that stimulated endothelial cell sprouting in a 3D model of angiogenesis in vitro. Phenotypic analysis of EDK and iPDK cells during the course of differentiation from hESCs and iPSCs revealed that both cell types progressively acquired pericyte lineage markers NG2, PDGFRβ, CD105, and CD73 and demonstrated transient induction of pericyte progenitor markers CD31, CD34, and Flk1/VEGFR2. Furthermore, when co-cultured with endothelial cells in 3D fibrin-based constructs, EDK and iPDK cells promoted self-assembly of vascular networks and vascular basement membrane deposition. Finally, transplantation of EDK cells into mice with hindlimb ischemia significantly reduced tissue necrosis and improved blood perfusion, demonstrating the potential of these cells to stimulate angiogenic responses in vivo. These findings demonstrate that stable populations of pericyte-like angiogenic cells can be generated with high efficiency from hESC and hiPSC using a directed differentiation approach. This provides new cell sources and opportunities for vascular tissue engineering and for the development of novel strategies in regenerative medicine.
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iPSCs activate an angiogenic response in mice with hindlimb ischemia.
“and to activate an angiogenic response in mice with hindlimb ischemia (157).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [157]
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Wound repair and regeneration: Mechanisms, signaling, and translation
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- Authors
- Shamis, Y., Silva, E. A., Hewitt, K. J., Brudno, Y., Levenberg, S., Mooney, D. J., & Garlick, J. A.
- Affiliations
- Tufts University (US)
- Harvard University (US)
- Technion – Israel Institute of Technology (IL)
- Corresponding author
- Garlick, Jonathan A.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-12-30
- Volume
- 8
- Issue
- 12
- Pages
- e83755
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3875480
- OpenAlex
- W2036353642
- Cited by
- 27
- References
- 35
- Citations by year
- 2023: 2 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 1 · 2014: 4
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health (5r01de017413-05)
- National Heart, Lung, and Blood Institute (HL069957, R01HL069957)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK098055)
- National Institute of Dental and Craniofacial Research (R01-DE017413, DE017413)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- fibroblasts, human embryonic stem cells, induced pluripotent stem cells, pericytes, angiogenesis, pericyte differentiation, vascular endothelial growth factor, hepatocyte growth factor, interleukin-8, PDGF-AA, angiopoietin-1, endothelial sprouting, 3D skin equivalents, vascular network formation, hindlimb ischemia, cell transplantation, vascular tissue engineering, regenerative medicine
- MeSH terms
- Animals, Cell Differentiation, Extremities, Fibroblasts, Humans, Ischemia, Biomarkers, Neovascularization, Physiologic, Pericytes, Proteome, Stem Cell Transplantation, Pluripotent Stem Cells, Endothelial Cells, Angiogenesis Inducing Agents, Mice, Embryonic Stem Cells, Induced Pluripotent Stem Cells
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