Enhanced trophic factor secretion by mesenchymal stem/stromal cells with Glycine-Histidine-Lysine (GHK)-modified alginate hydrogels
Open accessAbstract
Recombinant proteins and cytokines are under broad preclinical and clinical investigation to promote angiogenesis, but their success is limited by ineffective delivery, lack of long-term stability and excessive cost. Mesenchymal stem/stromal cells (MSC) secrete bioactive trophic factors, and thus, may provide an effective alternative to address these challenges. Glycine-Histidine-Lysine (GHK) is a peptide fragment of osteonectin, a matricellular protein with reported proangiogenic potential. We examined the capacity of GHK to up-regulate secretion of proangiogenic factors from human MSC in culture and when covalently coupled to alginate hydrogels. GHK had no apparent cytotoxic effects on MSC in culture over a wide range of concentrations. We detected a dose-dependent increase in vascular endothelial growth factor (VEGF) concentration in media conditioned by GHK-treated MSC, which increased endothelial cell proliferation, migration and tubule formation. We covalently coupled GHK to alginate using carbodiimide chemistry, and human MSC were entrapped in alginate hydrogels to assess VEGF secretion. Similar to monolayer culture, MSC responded to GHK-modified gels by secreting increased concentrations of VEGF and basic fibroblast growth factor compared to unmodified gels. The pre-treatment of MSC with antibodies to α6 and β1 integrins prior to entrapment in GHK-modified gels abrogated VEGF secretion, suggesting that the proangiogenic response of MSC was integrin-mediated. These data demonstrate that the proangiogenic potential of MSC can be significantly increased by the presentation of GHK with a biodegradable carrier, therefore increasing their clinical potential when used for tissue repair.
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GHK possesses antioxidant and anti-inflammatory effects.
“possesses antioxidant and anti-inflammatory effects”
From GHK and DNA: Resetting the human genome to health (2014) · cites this paper as [6]
GHK increases angiogenesis and nerve outgrowth.
“increases angiogenesis, and nerve outgrowth”
From GHK and DNA: Resetting the human genome to health (2014) · cites this paper as [6]
GHK increases cellular stemness and the secretion of trophic factors by mesenchymal stem cells.
“increases cellular stemness and the secretion of trophic factors by mesenchymal stem cells”
From GHK and DNA: Resetting the human genome to health (2014) · cites this paper as [6]
GHK increases collagen and glycosaminoglycans and stimulates synthesis of decorin.
“increases collagen and glycosaminoglycans, stimulates synthesis of decorin”
From GHK and DNA: Resetting the human genome to health (2014) · cites this paper as [6]
GHK improves wound healing and tissue regeneration in skin, hair follicles, stomach and intestinal linings, and boney tissue.
“It improves wound healing and tissue regeneration (skin, hair follicles, stomach and intestinal linings, and boney tissue)”
From GHK and DNA: Resetting the human genome to health (2014) · cites this paper as [6]
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- Authors
- Jose, S., Hughbanks, M. L., Binder, B. Y. K., Ingavle, G. C., & Leach, J. K.
- Affiliations
- University of California, Davis (US)
- University of California Davis Medical Center (US)
- Corresponding author
- Leach, J. Kent
- Venue
- Acta Biomaterialia
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 10
- Issue
- 5
- Pages
- 1955-1964
- ISSN
- 1742-7061 (ISSN-L)
- PMC
- PMC3976757
- OpenAlex
- W2061460113
- Cited by
- 73
- References
- 44
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 1 · 2021: 8 · 2020: 10 · 2019: 4 · 2018: 7 · 2017: 4 · 2016: 7 · 2015: 6 · 2014: 9 · 2013: 1
- FWCI
- 4.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Acta Biomaterialia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Department of the Army (W81XWH-10-1-0984)
- National Institutes of Health (NIH) (R21AG036963)
- California Institute for Regenerative Medicine University of California (CIRM T1-00006, CIRM TG2-01163)
- NSF (DBIO722538)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- mesenchymal stem cells, alginate hydrogel, angiogenesis, vascular endothelial growth factor, basic fibroblast growth factor, SPARC, integrin signaling, alpha6beta1 integrin, beta1 integrin, endothelial cell migration, endothelial tube formation, cell entrapment, biodegradable carriers, tissue repair
- MeSH terms
- Alginates, Cell Adhesion, Cell Movement, Cell Survival, Colony-Forming Units Assay, Hexuronic Acids, Humans, Mitogens, Oligopeptides, Integrins, Cell Death, Culture Media, Conditioned, Hydrogels, Glucuronic Acid, Vascular Endothelial Growth Factor A, Endothelial Cells, Mesenchymal Stem Cells
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