Activation of angiopoietin-1 signaling with engineering mesenchymal stem cells promoted efficient angiogenesis in diabetic wound healing
Abstract Background Vascular insufficiency is associated with the pathogenesis and therapeutic outcomes of diabetic foot ulcers (DFU). While mesenchymal stem cells (MSCs) hold potential for DFU treatment, further enhancement in promoting angiogenesis in the challenging DFU wounds is imperative. Meth...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-02-01
|
| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13287-025-04207-7 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850190574829699072 |
|---|---|
| author | Qiong Deng Fangzhou Du Shenzhen Pan Yuchen Xia Yuxin Zhu Jingzhong Zhang Chenglong Li Shuang Yu |
| author_facet | Qiong Deng Fangzhou Du Shenzhen Pan Yuchen Xia Yuxin Zhu Jingzhong Zhang Chenglong Li Shuang Yu |
| author_sort | Qiong Deng |
| collection | DOAJ |
| description | Abstract Background Vascular insufficiency is associated with the pathogenesis and therapeutic outcomes of diabetic foot ulcers (DFU). While mesenchymal stem cells (MSCs) hold potential for DFU treatment, further enhancement in promoting angiogenesis in the challenging DFU wounds is imperative. Methods The differential expression of pro- and anti-angiogenic factors during both normal and diabetic wound healing was compared using quantitative PCR. MSCs derived from the umbilical cord was prepared, and the engineered MSC (MSCANG1) overexpressing both the candidate pro-angiogenic gene, angiopoietin-1 (ANG1), and green fluorescent protein (GFP) was constructed using a lentiviral system. The pro-vascular stabilizing effects of MSCANG1 were assessed in primary endothelial cell cultures. Subsequently, MSCANG1 was transplanted into streptozotocin (STZ)-induced diabetic wound models to evaluate therapeutic effects on angiogenesis and wound healing. The underlying mechanisms were further examined both in vitro and in vivo. Results The comprehensive analysis of the temporal expression of pro- and anti-angiogenic factors revealed a consistent impairment in ANG1 expression throughout diabetic wound healing. MSCANG1 exhibited robust EGFP expression in 80% of cells, with overexpression and secretion of the ANG1 protein. MSCANG1 notably enhanced the survival and tubulogenesis of endothelial cells and promoted the expression of junction proteins, facilitating the establishment of functional vasculature with improved vascular leakage. Although MSCANG1 did not enhance the survival of engrafted MSCs in diabetic wounds, it significantly promoted angiogenesis in diabetic wound healing, fostering the establishment of stable vasculature during the healing process. Activation of the protein kinase B (Akt) pathway and suppression of proto-oncogene tyrosine kinase Src (Src) activity in MSCANG1-treated diabetic wounds confirmed efficient angiogenesis process. Consequently, epidermal and dermal reconstruction, as well as skin appendage regeneration were markedly accelerated in MSCANG1-treated diabetic wounds compared to MSC-treated wounds. Conclusion Treatment with MSCs alone promotes angiogenesis and DFU healing, while the engineering of MSCs with ANG1 provides substantial additional benefits to this therapeutic process. The engineering of MSCs with ANG1 presents a promising avenue for developing innovative strategies in managing DFU. |
| format | Article |
| id | doaj-art-626dc675b4b84c3daebaaa83ddbb1111 |
| institution | OA Journals |
| issn | 1757-6512 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj-art-626dc675b4b84c3daebaaa83ddbb11112025-08-20T02:15:15ZengBMCStem Cell Research & Therapy1757-65122025-02-0116111610.1186/s13287-025-04207-7Activation of angiopoietin-1 signaling with engineering mesenchymal stem cells promoted efficient angiogenesis in diabetic wound healingQiong Deng0Fangzhou Du1Shenzhen Pan2Yuchen Xia3Yuxin Zhu4Jingzhong Zhang5Chenglong Li6Shuang Yu7Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of SciencesSuzhou Institute of Biomedical Engineering and Technology, Chinese Academy of SciencesSuzhou Institute of Biomedical Engineering and Technology, Chinese Academy of SciencesSuzhou Institute of Biomedical Engineering and Technology, Chinese Academy of SciencesSuzhou Institute of Biomedical Engineering and Technology, Chinese Academy of SciencesSuzhou Institute of Biomedical Engineering and Technology, Chinese Academy of SciencesDepartment of Vascular Surgery, The Second Affiliated Hospital of Soochow UniversitySuzhou Institute of Biomedical Engineering and Technology, Chinese Academy of SciencesAbstract Background Vascular insufficiency is associated with the pathogenesis and therapeutic outcomes of diabetic foot ulcers (DFU). While mesenchymal stem cells (MSCs) hold potential for DFU treatment, further enhancement in promoting angiogenesis in the challenging DFU wounds is imperative. Methods The differential expression of pro- and anti-angiogenic factors during both normal and diabetic wound healing was compared using quantitative PCR. MSCs derived from the umbilical cord was prepared, and the engineered MSC (MSCANG1) overexpressing both the candidate pro-angiogenic gene, angiopoietin-1 (ANG1), and green fluorescent protein (GFP) was constructed using a lentiviral system. The pro-vascular stabilizing effects of MSCANG1 were assessed in primary endothelial cell cultures. Subsequently, MSCANG1 was transplanted into streptozotocin (STZ)-induced diabetic wound models to evaluate therapeutic effects on angiogenesis and wound healing. The underlying mechanisms were further examined both in vitro and in vivo. Results The comprehensive analysis of the temporal expression of pro- and anti-angiogenic factors revealed a consistent impairment in ANG1 expression throughout diabetic wound healing. MSCANG1 exhibited robust EGFP expression in 80% of cells, with overexpression and secretion of the ANG1 protein. MSCANG1 notably enhanced the survival and tubulogenesis of endothelial cells and promoted the expression of junction proteins, facilitating the establishment of functional vasculature with improved vascular leakage. Although MSCANG1 did not enhance the survival of engrafted MSCs in diabetic wounds, it significantly promoted angiogenesis in diabetic wound healing, fostering the establishment of stable vasculature during the healing process. Activation of the protein kinase B (Akt) pathway and suppression of proto-oncogene tyrosine kinase Src (Src) activity in MSCANG1-treated diabetic wounds confirmed efficient angiogenesis process. Consequently, epidermal and dermal reconstruction, as well as skin appendage regeneration were markedly accelerated in MSCANG1-treated diabetic wounds compared to MSC-treated wounds. Conclusion Treatment with MSCs alone promotes angiogenesis and DFU healing, while the engineering of MSCs with ANG1 provides substantial additional benefits to this therapeutic process. The engineering of MSCs with ANG1 presents a promising avenue for developing innovative strategies in managing DFU.https://doi.org/10.1186/s13287-025-04207-7Mesenchymal stem cellsAngiopoietin-1Diabetic Wound HealingAngiogenesisVascular leakage |
| spellingShingle | Qiong Deng Fangzhou Du Shenzhen Pan Yuchen Xia Yuxin Zhu Jingzhong Zhang Chenglong Li Shuang Yu Activation of angiopoietin-1 signaling with engineering mesenchymal stem cells promoted efficient angiogenesis in diabetic wound healing Stem Cell Research & Therapy Mesenchymal stem cells Angiopoietin-1 Diabetic Wound Healing Angiogenesis Vascular leakage |
| title | Activation of angiopoietin-1 signaling with engineering mesenchymal stem cells promoted efficient angiogenesis in diabetic wound healing |
| title_full | Activation of angiopoietin-1 signaling with engineering mesenchymal stem cells promoted efficient angiogenesis in diabetic wound healing |
| title_fullStr | Activation of angiopoietin-1 signaling with engineering mesenchymal stem cells promoted efficient angiogenesis in diabetic wound healing |
| title_full_unstemmed | Activation of angiopoietin-1 signaling with engineering mesenchymal stem cells promoted efficient angiogenesis in diabetic wound healing |
| title_short | Activation of angiopoietin-1 signaling with engineering mesenchymal stem cells promoted efficient angiogenesis in diabetic wound healing |
| title_sort | activation of angiopoietin 1 signaling with engineering mesenchymal stem cells promoted efficient angiogenesis in diabetic wound healing |
| topic | Mesenchymal stem cells Angiopoietin-1 Diabetic Wound Healing Angiogenesis Vascular leakage |
| url | https://doi.org/10.1186/s13287-025-04207-7 |
| work_keys_str_mv | AT qiongdeng activationofangiopoietin1signalingwithengineeringmesenchymalstemcellspromotedefficientangiogenesisindiabeticwoundhealing AT fangzhoudu activationofangiopoietin1signalingwithengineeringmesenchymalstemcellspromotedefficientangiogenesisindiabeticwoundhealing AT shenzhenpan activationofangiopoietin1signalingwithengineeringmesenchymalstemcellspromotedefficientangiogenesisindiabeticwoundhealing AT yuchenxia activationofangiopoietin1signalingwithengineeringmesenchymalstemcellspromotedefficientangiogenesisindiabeticwoundhealing AT yuxinzhu activationofangiopoietin1signalingwithengineeringmesenchymalstemcellspromotedefficientangiogenesisindiabeticwoundhealing AT jingzhongzhang activationofangiopoietin1signalingwithengineeringmesenchymalstemcellspromotedefficientangiogenesisindiabeticwoundhealing AT chenglongli activationofangiopoietin1signalingwithengineeringmesenchymalstemcellspromotedefficientangiogenesisindiabeticwoundhealing AT shuangyu activationofangiopoietin1signalingwithengineeringmesenchymalstemcellspromotedefficientangiogenesisindiabeticwoundhealing |