Acidic preconditioning of endothelial colony-forming cells (ECFC) promote vasculogenesis under proinflammatory and high glucose conditions in vitro and in vivo
Abstract Background We have previously demonstrated that acidic preconditioning of human endothelial colony-forming cells (ECFC) increased proliferation, migration, and tubulogenesis in vitro, and increased their regenerative potential in a murine model of hind limb ischemia without baseline disease...
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| Format: | Article |
| Language: | English |
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BMC
2018-05-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | http://link.springer.com/article/10.1186/s13287-018-0872-7 |
| _version_ | 1828465787672723456 |
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| author | Hebe Agustina Mena Paula Romina Zubiry Blandine Dizier Mirta Schattner Catherine Boisson-Vidal Soledad Negrotto |
| author_facet | Hebe Agustina Mena Paula Romina Zubiry Blandine Dizier Mirta Schattner Catherine Boisson-Vidal Soledad Negrotto |
| author_sort | Hebe Agustina Mena |
| collection | DOAJ |
| description | Abstract Background We have previously demonstrated that acidic preconditioning of human endothelial colony-forming cells (ECFC) increased proliferation, migration, and tubulogenesis in vitro, and increased their regenerative potential in a murine model of hind limb ischemia without baseline disease. We now analyze whether this strategy is also effective under adverse conditions for vasculogenesis, such as the presence of ischemia-related toxic molecules or diabetes, one of the main target diseases for cell therapy due to their well-known healing impairments. Methods Cord blood-derived CD34+ cells were seeded in endothelial growth culture medium (EGM2) and ECFC colonies were obtained after 14–21 days. ECFC were exposed at pH 6.6 (preconditioned) or pH 7.4 (nonpreconditioned) for 6 h, and then pH was restored at 7.4. A model of type 2 diabetes induced by a high-fat and high-sucrose diet was developed in nude mice and hind limb ischemia was induced in these animals by femoral artery ligation. A P value < 0.05 was considered statistically significant (by one-way analysis of variance). Results We found that acidic preconditioning increased ECFC adhesion and the release of pro-angiogenic molecules, and protected ECFC from the cytotoxic effects of monosodium urate crystals, histones, and tumor necrosis factor (TNF)α, which induced necrosis, pyroptosis, and apoptosis, respectively. Noncytotoxic concentrations of high glucose, TNFα, or their combination reduced ECFC proliferation, stromal cell-derived factor (SDF)1-driven migration, and tubule formation on a basement membrane matrix, whereas almost no inhibition was observed in preconditioned ECFC. In type 2 diabetic mice, intravenous administration of preconditioned ECFC significantly induced blood flow recovery at the ischemic limb as measured by Doppler, compared with the phosphate-buffered saline (PBS) and nonpreconditioned ECFC groups. Moreover, the histologic analysis of gastrocnemius muscles showed an increased vascular density and reduced signs of inflammation in the animals receiving preconditioned ECFC. Conclusions Acidic preconditioning improved ECFC survival and angiogenic activity in the presence of proinflammatory and damage signals present in the ischemic milieu, even under high glucose conditions, and increased their therapeutic potential for postischemia tissue regeneration in a murine model of type 2 diabetes. Collectively, our data suggest that acidic preconditioning of ECFC is a simple and inexpensive strategy to improve the effectiveness of cell transplantation in diabetes, where tissue repair is highly compromised. |
| first_indexed | 2024-12-11T03:40:06Z |
| format | Article |
| id | doaj.art-0de18faa036540fb9643ce31371362b0 |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-11T03:40:06Z |
| publishDate | 2018-05-01 |
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| spelling | doaj.art-0de18faa036540fb9643ce31371362b02022-12-22T01:22:10ZengBMCStem Cell Research & Therapy1757-65122018-05-019111310.1186/s13287-018-0872-7Acidic preconditioning of endothelial colony-forming cells (ECFC) promote vasculogenesis under proinflammatory and high glucose conditions in vitro and in vivoHebe Agustina Mena0Paula Romina Zubiry1Blandine Dizier2Mirta Schattner3Catherine Boisson-Vidal4Soledad Negrotto5Experimental Thrombosis Laboratory, Institute of Experimental Medicine (IMEX), National Academy of Medicine-CONICETExperimental Thrombosis Laboratory, Institute of Experimental Medicine (IMEX), National Academy of Medicine-CONICETUniversité Paris Descartes, Sorbonne Paris CitéExperimental Thrombosis Laboratory, Institute of Experimental Medicine (IMEX), National Academy of Medicine-CONICETUniversité Paris Descartes, Sorbonne Paris CitéExperimental Thrombosis Laboratory, Institute of Experimental Medicine (IMEX), National Academy of Medicine-CONICETAbstract Background We have previously demonstrated that acidic preconditioning of human endothelial colony-forming cells (ECFC) increased proliferation, migration, and tubulogenesis in vitro, and increased their regenerative potential in a murine model of hind limb ischemia without baseline disease. We now analyze whether this strategy is also effective under adverse conditions for vasculogenesis, such as the presence of ischemia-related toxic molecules or diabetes, one of the main target diseases for cell therapy due to their well-known healing impairments. Methods Cord blood-derived CD34+ cells were seeded in endothelial growth culture medium (EGM2) and ECFC colonies were obtained after 14–21 days. ECFC were exposed at pH 6.6 (preconditioned) or pH 7.4 (nonpreconditioned) for 6 h, and then pH was restored at 7.4. A model of type 2 diabetes induced by a high-fat and high-sucrose diet was developed in nude mice and hind limb ischemia was induced in these animals by femoral artery ligation. A P value < 0.05 was considered statistically significant (by one-way analysis of variance). Results We found that acidic preconditioning increased ECFC adhesion and the release of pro-angiogenic molecules, and protected ECFC from the cytotoxic effects of monosodium urate crystals, histones, and tumor necrosis factor (TNF)α, which induced necrosis, pyroptosis, and apoptosis, respectively. Noncytotoxic concentrations of high glucose, TNFα, or their combination reduced ECFC proliferation, stromal cell-derived factor (SDF)1-driven migration, and tubule formation on a basement membrane matrix, whereas almost no inhibition was observed in preconditioned ECFC. In type 2 diabetic mice, intravenous administration of preconditioned ECFC significantly induced blood flow recovery at the ischemic limb as measured by Doppler, compared with the phosphate-buffered saline (PBS) and nonpreconditioned ECFC groups. Moreover, the histologic analysis of gastrocnemius muscles showed an increased vascular density and reduced signs of inflammation in the animals receiving preconditioned ECFC. Conclusions Acidic preconditioning improved ECFC survival and angiogenic activity in the presence of proinflammatory and damage signals present in the ischemic milieu, even under high glucose conditions, and increased their therapeutic potential for postischemia tissue regeneration in a murine model of type 2 diabetes. Collectively, our data suggest that acidic preconditioning of ECFC is a simple and inexpensive strategy to improve the effectiveness of cell transplantation in diabetes, where tissue repair is highly compromised.http://link.springer.com/article/10.1186/s13287-018-0872-7Type 2 diabetesInflammationHuman endothelial colony forming cellsHind limb ischemiaAcidic preconditioningAngiogenesis |
| spellingShingle | Hebe Agustina Mena Paula Romina Zubiry Blandine Dizier Mirta Schattner Catherine Boisson-Vidal Soledad Negrotto Acidic preconditioning of endothelial colony-forming cells (ECFC) promote vasculogenesis under proinflammatory and high glucose conditions in vitro and in vivo Stem Cell Research & Therapy Type 2 diabetes Inflammation Human endothelial colony forming cells Hind limb ischemia Acidic preconditioning Angiogenesis |
| title | Acidic preconditioning of endothelial colony-forming cells (ECFC) promote vasculogenesis under proinflammatory and high glucose conditions in vitro and in vivo |
| title_full | Acidic preconditioning of endothelial colony-forming cells (ECFC) promote vasculogenesis under proinflammatory and high glucose conditions in vitro and in vivo |
| title_fullStr | Acidic preconditioning of endothelial colony-forming cells (ECFC) promote vasculogenesis under proinflammatory and high glucose conditions in vitro and in vivo |
| title_full_unstemmed | Acidic preconditioning of endothelial colony-forming cells (ECFC) promote vasculogenesis under proinflammatory and high glucose conditions in vitro and in vivo |
| title_short | Acidic preconditioning of endothelial colony-forming cells (ECFC) promote vasculogenesis under proinflammatory and high glucose conditions in vitro and in vivo |
| title_sort | acidic preconditioning of endothelial colony forming cells ecfc promote vasculogenesis under proinflammatory and high glucose conditions in vitro and in vivo |
| topic | Type 2 diabetes Inflammation Human endothelial colony forming cells Hind limb ischemia Acidic preconditioning Angiogenesis |
| url | http://link.springer.com/article/10.1186/s13287-018-0872-7 |
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