Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers
Abstract Background While rapid healing of diabetic foot ulcers (DFUs) is highly desirable to avoid infections, amputations and life-threatening complications, DFUs often respond poorly to standard treatment. GMP-manufactured skin-derived ABCB5+ mesenchymal stem cells (MSCs) might provide a new adju...
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| Format: | Article |
| Language: | English |
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BMC
2022-09-01
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| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13287-022-03156-9 |
| _version_ | 1828113125181751296 |
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| author | Andreas Kerstan Kathrin Dieter Elke Niebergall-Roth Sabrina Klingele Michael Jünger Christoph Hasslacher Georg Daeschlein Lutz Stemler Ulrich Meyer-Pannwitt Kristin Schubert Gerhard Klausmann Titus Raab Matthias Goebeler Korinna Kraft Jasmina Esterlechner Hannes M. Schröder Samar Sadeghi Seda Ballikaya Martin Gasser Ana M. Waaga-Gasser George F. Murphy Dennis P. Orgill Natasha Y. Frank Christoph Ganss Karin Scharffetter-Kochanek Markus H. Frank Mark A. Kluth |
| author_facet | Andreas Kerstan Kathrin Dieter Elke Niebergall-Roth Sabrina Klingele Michael Jünger Christoph Hasslacher Georg Daeschlein Lutz Stemler Ulrich Meyer-Pannwitt Kristin Schubert Gerhard Klausmann Titus Raab Matthias Goebeler Korinna Kraft Jasmina Esterlechner Hannes M. Schröder Samar Sadeghi Seda Ballikaya Martin Gasser Ana M. Waaga-Gasser George F. Murphy Dennis P. Orgill Natasha Y. Frank Christoph Ganss Karin Scharffetter-Kochanek Markus H. Frank Mark A. Kluth |
| author_sort | Andreas Kerstan |
| collection | DOAJ |
| description | Abstract Background While rapid healing of diabetic foot ulcers (DFUs) is highly desirable to avoid infections, amputations and life-threatening complications, DFUs often respond poorly to standard treatment. GMP-manufactured skin-derived ABCB5+ mesenchymal stem cells (MSCs) might provide a new adjunctive DFU treatment, based on their remarkable skin wound homing and engraftment potential, their ability to adaptively respond to inflammatory signals, and their wound healing-promoting efficacy in mouse wound models and human chronic venous ulcers. Methods The angiogenic potential of ABCB5+ MSCs was characterized with respect to angiogenic factor expression at the mRNA and protein level, in vitro endothelial trans-differentiation and tube formation potential, and perfusion-restoring capacity in a mouse hindlimb ischemia model. Finally, the efficacy and safety of ABCB5+ MSCs for topical adjunctive treatment of chronic, standard therapy-refractory, neuropathic plantar DFUs were assessed in an open-label single-arm clinical trial. Results Hypoxic incubation of ABCB5+ MSCs led to posttranslational stabilization of the hypoxia-inducible transcription factor 1α (HIF-1α) and upregulation of HIF-1α mRNA levels. HIF-1α pathway activation was accompanied by upregulation of vascular endothelial growth factor (VEGF) transcription and increase in VEGF protein secretion. Upon culture in growth factor-supplemented medium, ABCB5+ MSCs expressed the endothelial-lineage marker CD31, and after seeding on gel matrix, ABCB5+ MSCs demonstrated formation of capillary-like structures comparable with human umbilical vein endothelial cells. Intramuscularly injected ABCB5+ MSCs to mice with surgically induced hindlimb ischemia accelerated perfusion recovery as measured by laser Doppler blood perfusion imaging and enhanced capillary proliferation and vascularization in the ischemic muscles. Adjunctive topical application of ABCB5+ MSCs onto therapy-refractory DFUs elicited median wound surface area reductions from baseline of 59% (full analysis set, n = 23), 64% (per-protocol set, n = 20) and 67% (subgroup of responders, n = 17) at week 12, while no treatment-related adverse events were observed. Conclusions The present observations identify GMP-manufactured ABCB5+ dermal MSCs as a potential, safe candidate for adjunctive therapy of otherwise incurable DFUs and justify the conduct of a larger, randomized controlled trial to validate the clinical efficacy. Trial registration: ClinicalTrials.gov, NCT03267784, Registered 30 August 2017, https://clinicaltrials.gov/ct2/show/NCT03267784 |
| first_indexed | 2024-04-11T12:00:44Z |
| format | Article |
| id | doaj.art-4819e8d8b5ba4b6b811f719469da6383 |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-04-11T12:00:44Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-4819e8d8b5ba4b6b811f719469da63832022-12-22T04:24:51ZengBMCStem Cell Research & Therapy1757-65122022-09-0113112510.1186/s13287-022-03156-9Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcersAndreas Kerstan0Kathrin Dieter1Elke Niebergall-Roth2Sabrina Klingele3Michael Jünger4Christoph Hasslacher5Georg Daeschlein6Lutz Stemler7Ulrich Meyer-Pannwitt8Kristin Schubert9Gerhard Klausmann10Titus Raab11Matthias Goebeler12Korinna Kraft13Jasmina Esterlechner14Hannes M. Schröder15Samar Sadeghi16Seda Ballikaya17Martin Gasser18Ana M. Waaga-Gasser19George F. Murphy20Dennis P. Orgill21Natasha Y. Frank22Christoph Ganss23Karin Scharffetter-Kochanek24Markus H. Frank25Mark A. Kluth26Department of Dermatology, Venereology and Allergology, University Hospital WürzburgRHEACELL GmbH & Co. KGTICEBA GmbHTICEBA GmbHDepartment of Dermatology, University Hospital GreifswaldClinical Study Center St. JosefskrankenhausDepartment of Dermatology, University Hospital GreifswaldDiabetologikum DDG LudwigshafenDepartment of Clinical Research and Development, MARE Clinicmedamed GmbHStudienzentrum AschaffenburgDiabetologikum RaabDepartment of Dermatology, Venereology and Allergology, University Hospital WürzburgRHEACELL GmbH & Co. KGTICEBA GmbHRHEACELL GmbH & Co. KGTICEBA GmbHTICEBA GmbHDepartment of Surgery, University Hospital WürzburgDepartment of Surgery, University Hospital WürzburgDepartment of Dermatology, Brigham and Women’s Hospital, Harvard Medical SchoolDivision of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical SchoolDepartment of Medicine, VA Boston Healthcare SystemRHEACELL GmbH & Co. KGDepartment of Dermatology and Allergic Diseases, University HospitalDepartment of Dermatology, Brigham and Women’s Hospital, Harvard Medical SchoolRHEACELL GmbH & Co. KGAbstract Background While rapid healing of diabetic foot ulcers (DFUs) is highly desirable to avoid infections, amputations and life-threatening complications, DFUs often respond poorly to standard treatment. GMP-manufactured skin-derived ABCB5+ mesenchymal stem cells (MSCs) might provide a new adjunctive DFU treatment, based on their remarkable skin wound homing and engraftment potential, their ability to adaptively respond to inflammatory signals, and their wound healing-promoting efficacy in mouse wound models and human chronic venous ulcers. Methods The angiogenic potential of ABCB5+ MSCs was characterized with respect to angiogenic factor expression at the mRNA and protein level, in vitro endothelial trans-differentiation and tube formation potential, and perfusion-restoring capacity in a mouse hindlimb ischemia model. Finally, the efficacy and safety of ABCB5+ MSCs for topical adjunctive treatment of chronic, standard therapy-refractory, neuropathic plantar DFUs were assessed in an open-label single-arm clinical trial. Results Hypoxic incubation of ABCB5+ MSCs led to posttranslational stabilization of the hypoxia-inducible transcription factor 1α (HIF-1α) and upregulation of HIF-1α mRNA levels. HIF-1α pathway activation was accompanied by upregulation of vascular endothelial growth factor (VEGF) transcription and increase in VEGF protein secretion. Upon culture in growth factor-supplemented medium, ABCB5+ MSCs expressed the endothelial-lineage marker CD31, and after seeding on gel matrix, ABCB5+ MSCs demonstrated formation of capillary-like structures comparable with human umbilical vein endothelial cells. Intramuscularly injected ABCB5+ MSCs to mice with surgically induced hindlimb ischemia accelerated perfusion recovery as measured by laser Doppler blood perfusion imaging and enhanced capillary proliferation and vascularization in the ischemic muscles. Adjunctive topical application of ABCB5+ MSCs onto therapy-refractory DFUs elicited median wound surface area reductions from baseline of 59% (full analysis set, n = 23), 64% (per-protocol set, n = 20) and 67% (subgroup of responders, n = 17) at week 12, while no treatment-related adverse events were observed. Conclusions The present observations identify GMP-manufactured ABCB5+ dermal MSCs as a potential, safe candidate for adjunctive therapy of otherwise incurable DFUs and justify the conduct of a larger, randomized controlled trial to validate the clinical efficacy. Trial registration: ClinicalTrials.gov, NCT03267784, Registered 30 August 2017, https://clinicaltrials.gov/ct2/show/NCT03267784https://doi.org/10.1186/s13287-022-03156-9ABCB5Advanced-therapy medicinal productAngiogenesisChronic woundDiabetic foot ulcerMesenchymal stem cells |
| spellingShingle | Andreas Kerstan Kathrin Dieter Elke Niebergall-Roth Sabrina Klingele Michael Jünger Christoph Hasslacher Georg Daeschlein Lutz Stemler Ulrich Meyer-Pannwitt Kristin Schubert Gerhard Klausmann Titus Raab Matthias Goebeler Korinna Kraft Jasmina Esterlechner Hannes M. Schröder Samar Sadeghi Seda Ballikaya Martin Gasser Ana M. Waaga-Gasser George F. Murphy Dennis P. Orgill Natasha Y. Frank Christoph Ganss Karin Scharffetter-Kochanek Markus H. Frank Mark A. Kluth Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers Stem Cell Research & Therapy ABCB5 Advanced-therapy medicinal product Angiogenesis Chronic wound Diabetic foot ulcer Mesenchymal stem cells |
| title | Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers |
| title_full | Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers |
| title_fullStr | Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers |
| title_full_unstemmed | Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers |
| title_short | Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers |
| title_sort | translational development of abcb5 dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non healing diabetic foot ulcers |
| topic | ABCB5 Advanced-therapy medicinal product Angiogenesis Chronic wound Diabetic foot ulcer Mesenchymal stem cells |
| url | https://doi.org/10.1186/s13287-022-03156-9 |
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