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Hsiao PJ, Kao WY, Sung LC, Lin CY, Tsou LLA, Kao YH, Chou CL, Lee KT. The Role of Mesenchymal Stem Cells in Treating Diabetic Kidney Disease: Immunomodulatory Effects and Kidney Regeneration. Int J Med Sci 2025; 22:1720-1735. [PMID: 40093796 PMCID: PMC11905258 DOI: 10.7150/ijms.103806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 02/21/2025] [Indexed: 03/19/2025] Open
Abstract
Background: Diabetic kidney disease (DKD), also known as diabetic nephropathy (DN), is characterized by progressive glomerulosclerosis and chronic inflammation. The potential of mesenchymal stem cells (MSCs) in treating DKD could be explored. Methods: In this study, a streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) DKD mouse model was utilized to investigate the renoprotective potential of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) through immunohistochemical, histopathological, and biochemical analyses. Two separate experiments were conducted to assess the therapeutic efficacy of hUC-MSCs in a DN mouse model. The first experiment determined the optimal dose by assigning the body weight and food intake alterations, serum cytokines and kidney function changes post hUC-MSCs treatment. STZ-induced DKD mice were divided to four groups: DKD control and other three hUC-MSCs treatment groups (low-dose: 3x106, intermediate (middle)-dose: 1x107, and high-dose: 3x107 cells/kg), with intravenous administration at weeks 8, 10, and 12 over 14 weeks. The second experiment evaluated treatment frequency, with mice assigned to hUC-MSCs x1, x2, and x3 groups (3x107 cells/kg) administered at weeks 5, 6, and 7 across 12 weeks, assessing the kidney histology and morphometry changes. Results: In the first experiment, the body weight and food intake showed no significant alterations among the DN and other 3 hUC-MSCs treatment groups. Compared to the DKD control group, only high-dose hUC-MSCs (3x107 cells/kg) treatment group significantly reduced the levels of inflammatory cytokines (IL-1β, and TNF-α) (p <0.05). Additionally, the urine albumin-to-creatinine ratio (UACR) levels in the high-dose hUC-MSCs (3×10⁷ cells/kg) treatment group showed a decreasing trend compared to those in the DN control group (p = 0.06). In the second experiment, the hUC-MSCs x3 treatment group (3×10⁷ cells/kg) significantly alleviated kidney histopathology compared to the DKD group (p <0.05). Conclusion: hUC-MSCs treatment may present a potential avenue for reversing glomerulosclerosis and mitigating inflammation in DKD mice. The long-term therapeutic benefits of MSCs-based treatments in patients with DKD and other kidney diseases could be further investigated.
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Affiliation(s)
- Po-Jen Hsiao
- Division of Nephrology, Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defence Medical Centre, Taipei, Taiwan
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
| | - Wen-Yi Kao
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Li-Chin Sung
- Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Taipei Medical University-Research Centre of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
| | - Chia-Yi Lin
- Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Liam Li-An Tsou
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, NY, USA
- Biochemistry, Department of Chemistry, Hofstra University, Hempstead, New York, USA
| | - Yung-Hsi Kao
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
| | - Chu-Lin Chou
- Taipei Medical University-Research Centre of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Division of Nephrology, Department of Internal Medicine, Hsin Kuo Min Hospital, Taipei Medical University, Taoyuan City, Taiwan
| | - Kung-Ta Lee
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
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Mo J, Zhang J, Meng X, Wang F, Tang W, Liu Y, Fu L, Liang F, Mo Z. Inhibition of microRNA-139-5p Improves Fibroblasts Viability and Enhances Wound Repair in Diabetic Rats Through AP-1 (c-Fos/c-Jun). Diabetes Metab Syndr Obes 2025; 18:237-248. [PMID: 39901919 PMCID: PMC11789773 DOI: 10.2147/dmso.s496556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 01/22/2025] [Indexed: 02/05/2025] Open
Abstract
Introductions Diabetic foot ulcers (DFU) are notoriously difficult to heal, however, its underlying molecular mechanisms are unknown. MicroRNA-139-5p participates in various biological processes, including cancer and vascular endothelial injury, while its role in diabetic wound healing has not been reported. Methods Sprague-Dawley (SD) rats were intraperitoneally injected with streptozotocin and a 1.0 cm full-layer dorsal skin wound was made to establish a diabetic wound model. On days 1, 4, 7, and 10 after the wound was made, a solution containing microRNA-139-5p antagomir or control was injected along the dorsal edge of the wound. Wound healing was analyzed using Image J, histological analysis and molecular analysis. Skin tissues from 4 diabetic and 4 matched non-diabetic ulcer patients were obtained to detect microRNA-139-5p expression. In vitro, human skin fibroblasts were transfected with microRNA-139-5p inhibitors/mimics, the function of the fibroblasts was evaluated by CCK-8 assay and scratch assay, and AP-1 (c-Fos/c-Jun) was detected. Results Obviously elevated microRNA-139-5p expression was detected in the wound tissue of the rats with diabetes and patients with DFUs, and the microRNA-139-5p antagonist-treated diabetic wounds had faster healing rates. The pace of diabetic wound re-epithelialization and angiogenesis was accelerated, and the expression of AP-1 family members (c-Fos/c-Jun), and VEGF, PDGF was upregulated in the wound tissue of diabetic rats treated with topical microRNA-139-5p antagomir. In vitro, the expression of microRNA-139-5p was up-regulated in human skin fibroblasts induced by high glucose treatment, while the function of the cell proliferation and migration was promoted and the level of AP-1 (c-Fos/c-Jun) was increased after transfected with the microRNA-139-5p inhibitor, and vice versa. Our study further verified that microRNA-139-5p regulated the migration of human skin fibroblasts by modulating c-Fos. Conclusion Inhibiting microRNA-139-5p improves fibroblasts viability and promotes diabetic wound healing, suggesting that this may be a therapeutic strategy for diabetic foot ulcer.
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Affiliation(s)
- Jiake Mo
- Department of Endocrinology, Third Xiangya Hospital of Central South University, Changsha, Hunan Province, People’s Republic of China
- Diabetic Foot Research Center of Central South University, Changsha, Hunan Province, People’s Republic of China
| | - Jiaqi Zhang
- Department of Endocrinology, Third Xiangya Hospital of Central South University, Changsha, Hunan Province, People’s Republic of China
- Diabetic Foot Research Center of Central South University, Changsha, Hunan Province, People’s Republic of China
| | - Xubiao Meng
- Department of Endocrinology, Haikou People’s Hospital & Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, Hainan Province, People’s Republic of China
| | - Fang Wang
- Department of Endocrinology, Third Xiangya Hospital of Central South University, Changsha, Hunan Province, People’s Republic of China
- Diabetic Foot Research Center of Central South University, Changsha, Hunan Province, People’s Republic of China
| | - Weian Tang
- Department of Endocrinology, Third Xiangya Hospital of Central South University, Changsha, Hunan Province, People’s Republic of China
- Diabetic Foot Research Center of Central South University, Changsha, Hunan Province, People’s Republic of China
| | - Ying Liu
- Department of Endocrinology, Third Xiangya Hospital of Central South University, Changsha, Hunan Province, People’s Republic of China
- Diabetic Foot Research Center of Central South University, Changsha, Hunan Province, People’s Republic of China
| | - Lanfang Fu
- Department of Endocrinology, Haikou People’s Hospital & Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, Hainan Province, People’s Republic of China
| | - Fang Liang
- Department of Endocrinology, Xingtai People’s Hospital, Xingtai, Hebei Province, People’s Republic of China
| | - Zhaohui Mo
- Department of Endocrinology, Third Xiangya Hospital of Central South University, Changsha, Hunan Province, People’s Republic of China
- Diabetic Foot Research Center of Central South University, Changsha, Hunan Province, People’s Republic of China
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Qiu H, Zhang R, Si D, Shu Y, Liu J, Xia Y, Zhou O, Tan W, Yang K, Tian D, Luo Z, Liu E, Zou L, Fu Z, Peng D. Human Umbilical Cord-Mesenchymal Stem Cells Combined With Low Dosage Nintedanib Rather Than Using Alone Mitigates Pulmonary Fibrosis in Mice. Stem Cells Int 2025; 2025:9445735. [PMID: 39817116 PMCID: PMC11732289 DOI: 10.1155/sci/9445735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 11/15/2024] [Accepted: 12/16/2024] [Indexed: 01/18/2025] Open
Abstract
Pulmonary fibrosis (PF) is a lethal pathological change of fibrotic interstitial lung diseases (ILDs) with abundant fibroblasts proliferation after severely or continually alveolar epithelial cells (AECs) injury. Barely therapies are helpful for PF. Here we use bleomycin intratracheally injection to model PF with or without human umbilical cord-mesenchymal stem cells (hUC-MSCs) and/or nintedanib intervention. RNA-Seq followed with real-time PCR and western blot were used to find out the specific possible mechanisms of the effects of hUC-MSC and nintedanib on PF. Immunostaining, cell counting kit-8 (CCK-8), and 5-bromo-2'-deoxyuridine (BrdU) incorporation assay were used to detect the cell proliferation in vivo or in vitro separately. We found that hUC-MSCs alone had prophylactic, but not therapeutic effects on bleomycin induced mouse PF. Nevertheless, the combination therapy of hUC-MSCs and low-dose nintedanib significantly improved survival and reversed lung fibrosis in PF model mice. The factors secreted by hUC-MSCs have promotional effects on the proliferation both of fibroblasts and AECs. Nintedanib could hamper the facilitation of fibroblasts caused by hUC-MSCs without influence on AECs proliferation, which might be related with the inhibition on FGFR, PDGFR, and VEGFR activities. Our study indicated that the combination therapy of hUC-MSCs and nintedanib should be a promising strategy for PF.
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Affiliation(s)
- Huijun Qiu
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Rong Zhang
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Daozhu Si
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Yi Shu
- Centre for Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Jiang Liu
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Yunqiu Xia
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Ou Zhou
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Wen Tan
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Ke Yang
- Chongqing Engineering Research Centre of Stem Cell Therapy, Chongqing 400014, China
| | - Daiyin Tian
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Zhengxiu Luo
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Enmei Liu
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Lin Zou
- Centre for Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
- Chongqing Engineering Research Centre of Stem Cell Therapy, Chongqing 400014, China
| | - Zhou Fu
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
- Chongqing Engineering Research Centre of Stem Cell Therapy, Chongqing 400014, China
| | - Danyi Peng
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
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Hunt M, Torres M, Bachar-Wikstrom E, Wikstrom JD. Cellular and molecular roles of reactive oxygen species in wound healing. Commun Biol 2024; 7:1534. [PMID: 39562800 DOI: 10.1038/s42003-024-07219-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 11/05/2024] [Indexed: 11/21/2024] Open
Abstract
Wound healing is a highly coordinated spatiotemporal sequence of events involving several cell types and tissues. The process of wound healing requires strict regulation, and its disruption can lead to the formation of chronic wounds, which can have a significant impact on an individual's health as well as on worldwide healthcare expenditure. One essential aspect within the cellular and molecular regulation of wound healing pathogenesis is that of reactive oxygen species (ROS) and oxidative stress. Wounding significantly elevates levels of ROS, and an array of various reactive species are involved in modulating the wound healing process, such as through antimicrobial activities and signal transduction. However, as in many pathologies, ROS play an antagonistic pleiotropic role in wound healing, and can be a pathogenic factor in the formation of chronic wounds. Whilst advances in targeting ROS and oxidative stress have led to the development of novel pre-clinical therapeutic methods, due to the complex nature of ROS in wound healing, gaps in knowledge remain concerning the specific cellular and molecular functions of ROS in wound healing. In this review, we highlight current knowledge of these functions, and discuss the potential future direction of new studies, and how these pathways may be targeted in future pre-clinical studies.
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Affiliation(s)
- Matthew Hunt
- Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden
| | - Monica Torres
- Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden
- Dermato-Venereology Clinic, Karolinska University Hospital, Stockholm, Sweden
| | - Etty Bachar-Wikstrom
- Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden
| | - Jakob D Wikstrom
- Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
- Dermato-Venereology Clinic, Karolinska University Hospital, Stockholm, Sweden.
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Mahmoud NN, Hamad S, Shraim S. Inflammation-Modulating Biomedical Interventions for Diabetic Wound Healing: An Overview of Preclinical and Clinical Studies. ACS OMEGA 2024; 9:44860-44875. [PMID: 39554458 PMCID: PMC11561615 DOI: 10.1021/acsomega.4c02251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 05/15/2024] [Accepted: 07/01/2024] [Indexed: 11/19/2024]
Abstract
A diabetic wound exemplifies the challenge of chronic, nonhealing wounds. Elevated blood sugar levels in diabetes profoundly disrupt macrophage function, impairing crucial activities such as phagocytosis, immune response, cell migration, and blood vessel formation, all essential for effective wound healing. Moreover, the persistent presence of pro-inflammatory cytokines and reactive oxygen species, coupled with a decrease in anti-inflammatory factors, exacerbates the delay in wound healing associated with diabetes. This review emphasizes the dysfunctional inflammatory responses underlying diabetic wounds and explores preclinical studies of inflammation-modulating bioactives and biomaterials that show promise in expediting diabetic wound healing. Additionally, this review provides an overview of selected clinical studies employing biomaterials and bioactive molecules, shedding light on the gap between extensive preclinical research and limited clinical studies in this field.
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Affiliation(s)
- Nouf N. Mahmoud
- Faculty
of Pharmacy, Al-Zaytoonah University of
Jordan, Amman 11733, Jordan
- Department
of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha 2713, Qatar
| | - Salma Hamad
- International
School of London Qatar, Doha 18511, Qatar
| | - Sawsan Shraim
- Faculty
of Pharmacy, Al-Zaytoonah University of
Jordan, Amman 11733, Jordan
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Stelling-Férez J, Puente-Cuadrado JM, Álvarez-Yepes V, Alcaraz S, Tristante E, Hernández-Mármol I, Mompeán-Egea I, García-Hernández AM, Nicolás FJ. Refrigerated amniotic membrane maintains its therapeutic qualities for 48 hours. Front Bioeng Biotechnol 2024; 12:1455397. [PMID: 39569163 PMCID: PMC11576280 DOI: 10.3389/fbioe.2024.1455397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 10/10/2024] [Indexed: 11/22/2024] Open
Abstract
During wound healing, the migration of keratinocytes is critical for wound closure. The application of amniotic membrane (AM) on wounds with challenging contexts (e.g., chronification and diabetic foot ulcer) has proven very successful. However, the use of AM for clinical practice has several restraints when applied to patients; the most important restriction is preserving AM's therapeutic properties between its thawing and application onto the patient's wound. Moreover, AM collection and processing requires a cleanroom, together with specialized staff and equipment, and facilities that are not usually available in many hospitals and healthcare units. In this publication, we kept previously cryopreserved AM at different temperatures (37°C, 20°C, and 4°C) in different media (DMEM high glucose and saline solution with or without human albumin) and for long incubation time periods after thawing (24 h and 48 h). HaCaT keratinocytes and TGF-β1-chronified HaCaT keratinocytes were used to measure several parameters related to wound healing: migration, cell cycle arrest rescue, and the expression of key genes and migration-related proteins. Our findings indicate that AM kept in physiological saline solution at 4°C for 24 h or 48 h performed excellently in promoting HaCaT cell migration compared to AM that had been immediately thawed (0 h). Indeed, key proteins, extracellular signal-regulated kinase (ERK) and c-Jun, were induced by AM at 4°C in saline solution. Similarly, cell proliferation and different genes related to survival, inflammation, and senescence had, in all cases, the same response as to standard AM. These data suggest that the handling method in saline solution at 4°C does not interfere with AM's therapeutic properties.
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Affiliation(s)
- J Stelling-Férez
- Soluciones de Biología Molecular y Celular en Medicina Regenerativa, Health Sciences PhD Program, Universidad Católica de Murcia (UCAM), Murcia, Spain
- Regeneración Oncología Molecular y TGF-β, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - J M Puente-Cuadrado
- Regeneración Oncología Molecular y TGF-β, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - V Álvarez-Yepes
- Plataforma Sala Blanca Instituto Murciano de Investigación Biosanitaria (IMIB)-Pascual Parrilla, Murcia, Spain
| | - S Alcaraz
- Soluciones de Biología Molecular y Celular en Medicina Regenerativa, Health Sciences PhD Program, Universidad Católica de Murcia (UCAM), Murcia, Spain
- Regeneración Oncología Molecular y TGF-β, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - E Tristante
- Plataforma Sala Blanca Instituto Murciano de Investigación Biosanitaria (IMIB)-Pascual Parrilla, Murcia, Spain
| | - I Hernández-Mármol
- Regeneración Oncología Molecular y TGF-β, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - I Mompeán-Egea
- Plataforma Sala Blanca Instituto Murciano de Investigación Biosanitaria (IMIB)-Pascual Parrilla, Murcia, Spain
| | - A M García-Hernández
- Plataforma Sala Blanca Instituto Murciano de Investigación Biosanitaria (IMIB)-Pascual Parrilla, Murcia, Spain
- Hematopoietic Transplant and Cellular Therapy Unit, Virgen de la Arrixaca University Hospital, University of Murcia, Murcia, Spain
| | - F J Nicolás
- Regeneración Oncología Molecular y TGF-β, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
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Liu S, Zhao H, Jiang T, Wan G, Yan C, Zhang C, Yang X, Chen Z. The Angiogenic Repertoire of Stem Cell Extracellular Vesicles: Demystifying the Molecular Underpinnings for Wound Healing Applications. Stem Cell Rev Rep 2024; 20:1795-1812. [PMID: 39001965 DOI: 10.1007/s12015-024-10762-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/06/2024] [Indexed: 07/15/2024]
Abstract
Stem cells-derived extracellular vesicles (SC-EVs) have emerged as promising therapeutic agents for wound repair, recapitulating the biological effects of parent cells while mitigating immunogenic and tumorigenic risks. These EVs orchestrate wound healing processes, notably through modulating angiogenesis-a critical event in tissue revascularization and regeneration. This study provides a comprehensive overview of the multifaceted mechanisms underpinning the pro-angiogenic capacity of EVs from various stem cell sources within the wound microenvironment. By elucidating the molecular intricacies governing their angiogenic prowess, we aim to unravel the mechanistic repertoire underlying their remarkable potential to accelerate wound healing. Additionally, methods to enhance the angiogenic effects of SC-EVs, current limitations, and future perspectives are highlighted, emphasizing the significant potential of this rapidly advancing field in revolutionizing wound healing strategies.
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Affiliation(s)
- Shuoyuan Liu
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Huayuan Zhao
- Department of Urology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Tao Jiang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Gui Wan
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Chengqi Yan
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chi Zhang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaofan Yang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Zhenbing Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Xia Y, Wu P, Chen H, Chen Z. Advances in stem cell therapy for diabetic foot. Front Genet 2024; 15:1427205. [PMID: 39290985 PMCID: PMC11405205 DOI: 10.3389/fgene.2024.1427205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 08/14/2024] [Indexed: 09/19/2024] Open
Abstract
Diabetic Foot Ulcers (DFU) represent a grave complication often encountered in the advanced stages of diabetes mellitus. They frequently lead to recurrent hospitalizations and, in severe cases, can result in life-threatening conditions such as infections, gangrene, and even amputation Diabetic foot ulcers (DFU), as a serious complication in the late stage of diabetes mellitus, are prone to lead to repeated hospitalization, and in severe cases, infection, gangrene, and even amputation. Although there are many methods for treating diabetic foot, there is no clear and effective method to reduce the amputation rate of diabetic foot patients. In recent years, advancements in the understanding of stem cell therapy for the treatment of DFU have shed light on its potential as a novel therapeutic approach. In recent years, as the research on stem cell therapy for diabetic foot is gradually deepening, stem cells are expected to become a new therapeutic method for treating DFU in the future. Their therapeutic effects are through promoting angiogenesis, secreting paracrine factors, controlling inflammation, promoting collagen deposition, and regulating immunity, etc. Despite numerous studies confirming the efficacy of stem cell therapy in treating DFU, there is still a need for the establishment of standardized treatment protocols. Although numerous studies have shown that stem cell therapy for DFU is real and effective, there has not yet been a standardized treatment protocol. This article reviews studies related to stem cell therapy for DFU, looking at the mechanism of action, types of stem cells, and modes of administration.
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Affiliation(s)
- Yinfeng Xia
- Department of Burn and Plastic Surgery, Chongqing University Fuling Hospital, Chongqing University, Chongqing, China
| | - Ping Wu
- Department of Burn and Plastic Surgery, Chongqing University Fuling Hospital, Chongqing University, Chongqing, China
| | - Hong Chen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing MedicalUniversity, Chongqing, China
| | - Zhiyong Chen
- Department of Burn and Plastic Surgery, Chongqing University Fuling Hospital, Chongqing University, Chongqing, China
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Wan XX, Hu XM, Zhang Q, Xiong K. Pretreatment can alleviate programmed cell death in mesenchymal stem cells. World J Stem Cells 2024; 16:773-779. [PMID: 39219726 PMCID: PMC11362856 DOI: 10.4252/wjsc.v16.i8.773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/04/2024] [Accepted: 07/26/2024] [Indexed: 08/26/2024] Open
Abstract
In this editorial, we delved into the article titled "Cellular preconditioning and mesenchymal stem cell ferroptosis." This groundbreaking study underscores a pivotal discovery: Ferroptosis, a type of programmed cell death, drastically reduces the viability of donor mesenchymal stem cells (MSCs) after engraftment, thereby undermining the therapeutic value of cell-based therapies. Furthermore, the article proposes that by manipulating ferroptosis mechanisms through preconditioning, we can potentially enhance the survival rate and functionality of MSCs, ultimately amplifying their therapeutic potential. Given the crucial role ferroptosis plays in shaping the therapeutic outcomes of MSCs, we deem it imperative to further investigate the intricate interplay between programmed cell death and the therapeutic effectiveness of MSCs.
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Affiliation(s)
- Xin-Xing Wan
- Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Xi-Min Hu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Qi Zhang
- Department of Anatomy and Neurobiology, Central South University, Changsha 410000, Hunan Province, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China.
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10
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Sirpilla O, Sakemura RL, Hefazi M, Huynh TN, Can I, Girsch JH, Tapper EE, Cox MJ, Schick KJ, Manriquez-Roman C, Yun K, Stewart CM, Ogbodo EJ, Kimball BL, Mai LK, Gutierrez-Ruiz OL, Rodriguez ML, Gluscevic M, Larson DP, Abel AM, Wierson WA, Olivier G, Siegler EL, Kenderian SS. Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression. Nat Biomed Eng 2024; 8:443-460. [PMID: 38561490 DOI: 10.1038/s41551-024-01195-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 03/04/2024] [Indexed: 04/04/2024]
Abstract
Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals' symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression.
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Affiliation(s)
- Olivia Sirpilla
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA
| | - R Leo Sakemura
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Mehrdad Hefazi
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Truc N Huynh
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Ismail Can
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA
| | - James H Girsch
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Erin E Tapper
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Michelle J Cox
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Kendall J Schick
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Claudia Manriquez-Roman
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Kun Yun
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Carli M Stewart
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA
| | - Ekene J Ogbodo
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Brooke L Kimball
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Long K Mai
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Omar L Gutierrez-Ruiz
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Makena L Rodriguez
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Martina Gluscevic
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Daniel P Larson
- Division of Hematopathology, Mayo Clinic, Rochester, MN, USA
| | - Alex M Abel
- LifEngine Animal Health Laboratories Incorporated, Rochester, MN, USA
| | - Wesley A Wierson
- LifEngine Animal Health Laboratories Incorporated, Rochester, MN, USA
| | - Gloria Olivier
- Department of Business Development, Mayo Clinic, Rochester, MN, USA
| | - Elizabeth L Siegler
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Saad S Kenderian
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA.
- Division of Hematology, Mayo Clinic, Rochester, MN, USA.
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
- Department of Immunology, Mayo Clinic, Rochester, MN, USA.
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11
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Wan XX, Hu XM, Xiong K. Multiple pretreatments can effectively improve the functionality of mesenchymal stem cells. World J Stem Cells 2024; 16:58-63. [PMID: 38455107 PMCID: PMC10915953 DOI: 10.4252/wjsc.v16.i2.58] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 12/27/2023] [Accepted: 01/30/2024] [Indexed: 02/26/2024] Open
Abstract
In this editorial, we offer our perspective on the groundbreaking study entitled "Hypoxia and inflammatory factor preconditioning enhances the immunosuppressive properties of human umbilical cord mesenchymal stem cells", recently published in World Journal of Stem Cells. Despite over three decades of research on the clinical application of mesenchymal stem cells (MSCs), only a few therapeutic products have made it to clinical use, due to multiple preclinical and clinical challenges yet to be addressed. The study proved the hypoxia and inflammatory factor preconditioning led to higher immunosuppressive effects of MSCs without damaging their biological characteristics, which revealed the combination of inflammatory factors and hypoxic preconditioning offers a promising approach to enhance the function of MSCs. As we delve deeper into the intricacies of pretreatment methodologies, we anticipate a transformative shift in the landscape of MSC-based therapies, ultimately contributing to improved patient outcomes and advancing the field as a whole.
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Affiliation(s)
- Xin-Xing Wan
- Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Xi-Min Hu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China.
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12
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Panda D, Nayak S. Stem Cell-Based Tissue Engineering Approaches for Diabetic Foot Ulcer: a Review from Mechanism to Clinical Trial. Stem Cell Rev Rep 2024; 20:88-123. [PMID: 37867186 DOI: 10.1007/s12015-023-10640-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2023] [Indexed: 10/24/2023]
Abstract
Diabetic foot ulcer (DFU) is a complication from incomplete or prolonged wound healing, at times requires amputation, putting substantial health and socioeconomic burden. Wound healing is a dynamic overlapping process that can be regulated by arrays of molecular factors showing redundancy in function. However, dysregulation in the mechanism of angiogenesis, extra cellular matrix (ECM) formation and immune modulation are the major causes for impair wound healing in hyperglycaemic patients. Despite development of wound care research, there is a lack of well-accepted targeted therapy with multidisciplinary approach for DFU treatment. Stem cell therapy holds a promising outcome both in preclinical and clinical trials because of its ability to promote healing via regeneration and specialized tissue differentiation. Among different types of stem cells, regenerative potential of mesenchymal stem cell (MSC) is well demonstrated in both experimental and clinical trial. Still there is a huge knowledge gap among medical practitioners for deciding the best stem cell source, administration route, and safety. This review strengthens the fact that why stem cell therapy is a promising candidate to treat DFU and cited multiple tissue engineering and biomaterial-based approaches for delivering stem cells and their aftermath paracrine events. Based on the pre-clinical and clinical studies, the review tried to come up with optimum stem cell source and delivery route for the treatment of DFU. At last, the review glances on possible direction to enhance therapeutics strategy for the same, including different approaches like: phytocompounds, exosomes, scaffold geometry, cell preconditioning and licensing etc.
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Affiliation(s)
- Debarchan Panda
- Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Sunita Nayak
- Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
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13
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Doron G, Wood LB, Guldberg RE, Temenoff JS. Poly(ethylene glycol)-Based Hydrogel Microcarriers Alter Secretory Activity of Genetically Modified Mesenchymal Stromal Cells. ACS Biomater Sci Eng 2023; 9:6282-6292. [PMID: 37906515 PMCID: PMC10646834 DOI: 10.1021/acsbiomaterials.3c00954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/11/2023] [Accepted: 10/17/2023] [Indexed: 11/02/2023]
Abstract
In order to scale up culture therapeutic cells, such as mesenchymal stromal cells (MSCs), culture in suspension bioreactors using microcarriers (μCs) is preferred. However, the impact of microcarrier type on the resulting MSC secretory activity has not been investigated. In this study, two poly(ethylene glycol) hydrogel formulations with different swelling ratios (named "stiffer" and "softer") were fabricated as μC substrates to culture MSCs and MSCs genetically modified to express the interleukin-1 receptor antagonist (IL-1Ra-MSCs). Changes in cell number, secretory and angiogenic activity, and changes in MAPK signaling were evaluated when cultured on hydrogel μCs, as well as on tissue culture plastic-based Synthemax μCs. We demonstrated that culture on stiffer μCs increased secretion of IL-1Ra compared to culture on Synthemax μCs by IL-1Ra-MSCs by 1.2- to 1.6-fold, as well as their in vitro angiogenic activity, compared to culture on Synthemax μCs, while culture on both stiffer and softer μCs altered the secretion of several other factors compared to culture on Synthemax μCs. Changes in angiogenic activity corresponded with increased gene expression and secretion of hepatocyte growth factor by MSCs cultured on softer μCs by 2.5- to 6-fold compared to MSCs cultured on Synthemax μCs. Quantification of phosphoprotein signaling with the MAPK pathway revealed broad reduction of pathway activation by IL-1Ra-MSCs cultured on both stiffer and softer μCs compared to Synthemax, where phosphorylated c-Jun, ATF2, and MEK1 were reduced specifically on softer μCs. Overall, this study showed that μC surfaces can influence the secretory activity of genetically modified MSCs and identified associated changes in MAPK pathway signaling, which is a known central regulator of cytokine secretion.
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Affiliation(s)
- Gilad Doron
- Wallace
H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory University, 313 Ferst Dr. NW, Atlanta, Georgia 30332, United States
| | - Levi B. Wood
- Wallace
H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory University, 313 Ferst Dr. NW, Atlanta, Georgia 30332, United States
- George
W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 801 Ferst Dr. NW, Atlanta, Georgia 30318, United States
- Parker
H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr. NW, Atlanta, Georgia 30332, United States
| | - Robert E. Guldberg
- Knight
Campus for Accelerating Scientific Impact, University of Oregon, 6231 University of Oregon, Eugene, Oregon 97403, United States
| | - Johnna S. Temenoff
- Wallace
H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory University, 313 Ferst Dr. NW, Atlanta, Georgia 30332, United States
- Parker
H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr. NW, Atlanta, Georgia 30332, United States
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14
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Gu R, Zhou H, Zhang Z, Lv Y, Pan Y, Li Q, Shi C, Wang Y, Wei L. Research progress related to thermosensitive hydrogel dressings in wound healing: a review. NANOSCALE ADVANCES 2023; 5:6017-6037. [PMID: 37941954 PMCID: PMC10629053 DOI: 10.1039/d3na00407d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 07/27/2023] [Indexed: 11/10/2023]
Abstract
Wound healing is a dynamic and complex process in which the microenvironment at the wound site plays an important role. As a common material for wound healing, dressings accelerate wound healing and prevent external wound infections. Hydrogels have become a hot topic in wound-dressing research because of their high water content, good biocompatibility, and adjustable physical and chemical properties. Intelligent hydrogel dressings have attracted considerable attention because of their excellent environmental responsiveness. As smart polymer hydrogels, thermosensitive hydrogels can respond to small temperature changes in the environment, and their special properties make them superior to other hydrogels. This review mainly focuses on the research progress in thermosensitive intelligent hydrogel dressings for wound healing. Polymers suitable for hydrogel formation and the appropriate molecular design of the hydrogel network to achieve thermosensitive hydrogel properties are discussed, followed by the application of thermosensitive hydrogels as wound dressings. We also discuss the future perspectives of thermosensitive hydrogels as wound dressings and provide systematic theoretical support for wound healing.
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Affiliation(s)
- Ruting Gu
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University Qingdao 266000 China
| | - Haiqing Zhou
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University Qingdao 266000 China
| | - Zirui Zhang
- Emergency Departments, The Affiliated Hospital of Qingdao University Qingdao 266000 China
| | - Yun Lv
- School of Nursing, Qingdao University Qingdao 266000 China
| | - Yueshuai Pan
- Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University Qingdao 266000 China
| | - Qianqian Li
- Ophthalmology Department, The Affiliated Hospital of Qingdao University Qingdao 266000 China
| | - Changfang Shi
- Department of Spinal Surgery, The Affiliated Hospital of Qingdao University Qingdao 266000 China
| | - Yanhui Wang
- Department of Oral Implantology, The Affiliated Hospital of Qingdao University Qingdao 266000 China
| | - Lili Wei
- Office of the Dean, The Affiliated Hospital of Qingdao University Qingdao 266000 China
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15
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Stelling-Férez J, López-Miranda S, Gabaldón JA, Nicolás FJ. Oleanolic Acid Complexation with Cyclodextrins Improves Its Cell Bio-Availability and Biological Activities for Cell Migration. Int J Mol Sci 2023; 24:14860. [PMID: 37834307 PMCID: PMC10573973 DOI: 10.3390/ijms241914860] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 09/26/2023] [Accepted: 09/29/2023] [Indexed: 10/15/2023] Open
Abstract
Wound healing is a complex process to restore skin. Plant-derived bioactive compounds might be a source of substances for the treatment of wounds stalled in a non-resolving stage of wound healing. Oleanolic acid (OA), a pentacyclic triterpene, has shown favorable wound healing properties both in vitro and in vivo. Unfortunately, OA cannot be solubilized in aqueous media, and it needs to be helped by the use of dimethyl sulfoxide (DMSO). In this paper, we have shown that cyclodextrins (CDs) are a good alternative to DMSO as agents to deliver OA to cells, providing better features than DMSO. Cyclodextrins are natural macromolecules that show a unique tridimensional structure that can encapsulate a wide variety of hydrophobic compounds. We have studied the cyclodextrin-encapsulated form of OA with OA/DMSO, comparing their stability, biological properties for cell migration, and cell viability. In addition, detailed parameters related to cell migration and cytoskeletal reorganization have been measured and compared. Our results show that OA-encapsulateds compound exhibit several advantages when compared to non-encapsulated OA in terms of chemical stability, migration enhancement, and preservation of cell viability.
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Affiliation(s)
- Javier Stelling-Férez
- Department of Nutrition and Food Technology, Health Sciences PhD Program, Universidad Católica de San Antonio Murcia (UCAM), Campus de los Jerónimos n°135, Guadalupe, 30107 Murcia, Spain; (J.S.-F.); (S.L.-M.); (J.A.G.)
- Regeneration, Molecular Oncology and TGF-β, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, 30120 Murcia, Spain
| | - Santiago López-Miranda
- Department of Nutrition and Food Technology, Health Sciences PhD Program, Universidad Católica de San Antonio Murcia (UCAM), Campus de los Jerónimos n°135, Guadalupe, 30107 Murcia, Spain; (J.S.-F.); (S.L.-M.); (J.A.G.)
| | - José Antonio Gabaldón
- Department of Nutrition and Food Technology, Health Sciences PhD Program, Universidad Católica de San Antonio Murcia (UCAM), Campus de los Jerónimos n°135, Guadalupe, 30107 Murcia, Spain; (J.S.-F.); (S.L.-M.); (J.A.G.)
| | - Francisco José Nicolás
- Regeneration, Molecular Oncology and TGF-β, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, 30120 Murcia, Spain
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16
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Zhu XL, Hu DY, Zeng ZX, Jiang WW, Chen TY, Chen TC, Liao WQ, Lei WZ, Fang WJ, Pan WH. XB130 inhibits healing of diabetic skin ulcers through the PI3K/Akt signalling pathway. World J Diabetes 2023; 14:1369-1384. [PMID: 37771334 PMCID: PMC10523235 DOI: 10.4239/wjd.v14.i9.1369] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/06/2023] [Accepted: 08/02/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND Diabetic skin ulcers, a significant global healthcare burden, are mainly caused by the inhibition of cell proliferation and impaired angiogenesis. XB130 is an adaptor protein that regulates cell proliferation and migration. However, the role of XB130 in the development of diabetic skin ulcers remains unclear. AIM To investigate whether XB130 can regulate the inhibition of proliferation and vascular damage induced by high glucose. Additionally, we aim to determine whether XB130 is involved in the healing process of diabetic skin ulcers, along with its molecular mechanisms. METHODS We conducted RNA-sequencing analysis to identify the key genes involved in diabetic skin ulcers. We investigated the effects of XB130 on wound healing using histological analyses. In addition, we used reverse transcription-quantitative polymerase chain reaction, Western blot, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, immunofluorescence, wound healing, and tubule formation experiments to investigate their effects on cellular processes in human umbilical vein endothelial cells (HUVECs) stimulated with high glucose. Finally, we performed functional analysis to elucidate the molecular mechanisms underlying diabetic skin ulcers. RESULTS RNA-sequencing analysis showed that the expression of XB130 was up-regulated in the tissues of diabetic skin ulcers. Knockdown of XB130 promoted the healing of skin wounds in mice, leading to an accelerated wound healing process and shortened wound healing time. At the cellular level, knockdown of XB130 alleviated high glucose-induced inhibition of cell proliferation and angiogenic impairment in HUVECs. Inhibition of the PI3K/Akt pathway removed the proliferative effects and endothelial protection mediated by XB130. CONCLUSION The findings of this study indicated that the expression of XB130 is up-regulated in high glucose-stimulated diabetic skin ulcers and HUVECs. Knockdown of XB130 promotes cell proliferation and angiogenesis via the PI3K/Akt signalling pathway, which accelerates the healing of diabetic skin ulcers.
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Affiliation(s)
- Xin-Lin Zhu
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Dong-Ying Hu
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Zhao-Xiang Zeng
- Department of Vascular Surgery, Department of Vascular Surgery, Changhai Hospital, Navy Medical University, Shanghai 20003, China
| | - Wei-Wei Jiang
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Tian-Yang Chen
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Tian-Cheng Chen
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Wan-Qing Liao
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Wen-Zhi Lei
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Wen-Jie Fang
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Wei-Hua Pan
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
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17
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Li L, Li J, Guan H, Oishi H, Takahashi S, Zhang C. Human umbilical cord mesenchymal stem cells in diabetes mellitus and its complications: applications and research advances. Int J Med Sci 2023; 20:1492-1507. [PMID: 37790847 PMCID: PMC10542192 DOI: 10.7150/ijms.87472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 08/22/2023] [Indexed: 10/05/2023] Open
Abstract
Diabetes mellitus and its complications pose a major threat to global health and affect the quality of life and life expectancy of patients. Currently, the application of traditional therapeutic drugs for diabetes mellitus has great limitations and can only temporarily control blood glucose but not fundamentally cure it. Mesenchymal stem cells, as pluripotent stromal cells, have multidirectional differentiation potential, high self-renewal, immune regulation, and low immunogenicity, which provide a new idea and possible development direction for diabetes mellitus treatment. Regenerative medicine with mesenchymal stem cells treatment as the core treatment will become another treatment option for diabetes mellitus after traditional treatment. Recently, human umbilical cord mesenchymal stem cells have been widely used in basic and clinical research on diabetes mellitus and its complications because of their abundance, low ethical controversy, low risk of infection, and high proliferation and differentiation ability. This paper reviews the therapeutic role and mechanism of human umbilical cord mesenchymal stem cells in diabetes mellitus and its complications and highlights the challenges faced by the clinical application of human umbilical cord mesenchymal stem cells to provide a more theoretical basis for the application of human umbilical cord mesenchymal stem cells in diabetes mellitus patients.
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Affiliation(s)
- Luyao Li
- Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
| | - Jicui Li
- Department of Nephrology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
| | - Haifei Guan
- Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
| | - Hisashi Oishi
- Department of Comparative and Experimental Medicine, Nagoya City University Graduate 24 School of Medical Sciences, Aichi 467-8601, Nagoya, Japan
| | - Satoru Takahashi
- Institute of Basic Medical Sciences and Laboratory Animal Resource Center, University of Tsukuba, Ibaraki 305-8575, Tsukuba, Japan
| | - Chuan Zhang
- Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
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18
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Shu F, Lu J, Zhang W, Huang H, Lin J, Jiang L, Liu W, Liu T, Xiao S, Zheng Y, Xia Z. JAM-A Overexpression in Human Umbilical Cord-Derived Mesenchymal Stem Cells Accelerated the Angiogenesis of Diabetic Wound By Enhancing Both Paracrine Function and Survival of Mesenchymal Stem Cells. Stem Cell Rev Rep 2023; 19:1554-1575. [PMID: 37060532 DOI: 10.1007/s12015-023-10518-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2023] [Indexed: 04/16/2023]
Abstract
Mesenchymal stem cells (MSCs) is promising in promoting wound healing mainly due to their paracrine function. Nonetheless, the transplanted MSCs presented poor survival with cell dysfunction and paracrine problem in diabetic environment, thus limiting their therapeutic efficacy and clinical application. JAM-A, an adhesion molecule, has been reported to play multi-functional roles in diverse cells. We therefore investigated the potential effect of JAM-A on MSCs under diabetic environment and explored the underlying mechanism. Indeed, high-glucose condition inhibited MSCs viability and JAM-A expression. However, JAM-A abnormality was rescued by lentivirus transfection and JAM-A overexpression promoted MSCs proliferation, migration and adhesion under hyperglycemia. Moreover, JAM-A overexpression attenuated high-glucose-induced ROS production and MSCs apoptosis. The bio-effects of JAM-A on MSCs under hyperglycemia were confirmed by RNA-seq with enrichment analyses. Moreover, Luminex chip results showed JAM-A overexpression dramatically upregulated PDGF-BB and VEGF in the supernatant of MSCs, which was verified by RT-qPCR and western blotting. The supernatant was further found to facilitate HUVECs proliferation, migration and angiogenesis under hyperglycemia. In vivo experiments revealed JAM-A overexpression significantly enhanced MSCs survival, promoted wound angiogenesis, and thus accelerated diabetic wound closure, partially by enhancing PDGF-BB and VEGF expression. This study firstly demonstrated that JAM-A expression of MSCs was inhibited upon high-glucose stimulation. JAM-A overexpression alleviated high-glucose-induced MSCs dysfunction, enhanced their anti-oxidative capability, protected MSCs from hyperglycemia-induced apoptosis and improved their survival, thus strengthening MSCs paracrine function to promote angiogenesis and significantly accelerating diabetic wound healing, which offers a promising strategy to maximize MSCs-based therapy in diabetic wound.
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Affiliation(s)
- Futing Shu
- Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People's Republic of China
| | - Jianyu Lu
- Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People's Republic of China
| | - Wei Zhang
- Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People's Republic of China
| | - Hongchao Huang
- Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People's Republic of China
| | - Jiezhi Lin
- Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People's Republic of China
| | - Luofeng Jiang
- Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People's Republic of China
| | - Wenzhang Liu
- Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People's Republic of China
| | - Tianyi Liu
- Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People's Republic of China
| | - Shichu Xiao
- Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People's Republic of China.
| | - Yongjun Zheng
- Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People's Republic of China.
| | - Zhaofan Xia
- Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People's Republic of China.
- Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai, 200433, People's Republic of China.
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19
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Liu Y, Mo J, Liang F, Jiang S, Xiong J, Meng X, Mo Z. Pien-tze-huang promotes wound healing in streptozotocin-induced diabetes models associated with improving oxidative stress via the Nrf2/ARE pathway. Front Pharmacol 2023; 14:1062664. [PMID: 36713837 PMCID: PMC9878590 DOI: 10.3389/fphar.2023.1062664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 01/02/2023] [Indexed: 01/13/2023] Open
Abstract
Diabetic foot ulcers are a serious complication of diabetes, with high mortality and a lack of effective clinical treatment, which leads to a considerable financial burden. Pien-Tze-Huang (PZH) is a Chinese traditional medicine with a long history that has been found to be an effective and convenient treatment for inflammatory diseases such as skin abscesses and ulcers. In this study, we assessed the effects of PZH on diabetic wounds and the underlying mechanisms. The wounds were established on the backs of streptozotocin-induced type 1 diabetic rats and type 2 diabetic mouse models. We found that PZH treatment used locally or by gavage significantly promoted wound healing, accelerated re-epithelialization and vasculature in the wound tissue, upregulated the expression of the growth factors VEGF-A, PDGF, and EGF, and activated the Nrf2/ARE pathway in the wound tissue. In vitro assays showed that PZH improved the proliferation, migration and angiogenic function of human umbilical vein endothelial cells (HUVECs) cultured in palmitic acid, reduced the expression of the apoptotic proteins p53, Bax, and cleaved-caspase3, and activated Nrf2/ARE signaling; however, these protective effects were abrogated after Nrf2 was knocked down by specific siRNA. In addition, the levels of the serum inflammatory cytokines IL-1β, TNF-α, and IL-6 were reduced after PZH gavage treatment. In conclusion, the positive role of PZH in diabetic wound healing might be related to the activation of the Nrf2/ARE pathway to regulate the level of oxidative stress in vivo and increase the expression of growth factors to improve angiogenesis.
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Affiliation(s)
- Ying Liu
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, Hunan, China
| | - Jiake Mo
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, Hunan, China
| | - Fang Liang
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, Hunan, China
| | - Siwei Jiang
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, Hunan, China
| | - Jing Xiong
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, Hunan, China
| | - Xubiao Meng
- Department of Endocrinology, Haikou people’s Hospital & Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, Hainan, China
| | - Zhaohui Mo
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, Hunan, China,*Correspondence: Zhaohui Mo,
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20
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Mahmoudvand G, Karimi Rouzbahani A, Razavi ZS, Mahjoor M, Afkhami H. Mesenchymal stem cell therapy for non-healing diabetic foot ulcer infection: New insight. Front Bioeng Biotechnol 2023; 11:1158484. [PMID: 37122856 PMCID: PMC10133463 DOI: 10.3389/fbioe.2023.1158484] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 03/31/2023] [Indexed: 05/02/2023] Open
Abstract
Diabetic foot ulcer (DFU) is considered the most catastrophic complication of diabetes mellitus (DM), leading to repeated hospitalizations, infection, gangrene, and finally amputation of the limb. In patients suffering from diabetes mellitus, the wound-healing process is impaired due to various factors such as endothelial dysfunction and synthesis of advanced glycation end-products, hence, conventional therapeutic interventions might not be effective. With increasing therapeutic applications of mesenchymal stem cells (MSCs) in recent years, their potential as a method for improving the wound-healing process has gained remarkable attention. In this field, mesenchymal stem cells exert their beneficial effects through immunomodulation, differentiation into the essential cells at the site of ulcers, and promoting angiogenesis, among others. In this article, we review cellular and molecular pathways through which mesenchymal stem cell therapy reinforces the healing process in non-healing Diabetic foot ulcers.
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Affiliation(s)
- Golnaz Mahmoudvand
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Arian Karimi Rouzbahani
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Zahra Sadat Razavi
- Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohamad Mahjoor
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Afkhami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
- *Correspondence: Hamed Afkhami,
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21
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Liang F, Luo YF, Guo Z, Qian Q, Meng XB, Mo ZH. MicroRNA-139-5p mediates BMSCs impairment in diabetes by targeting HOXA9/c-Fos. FASEB J 2023; 37:e22697. [PMID: 36527387 DOI: 10.1096/fj.202201059r] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 10/13/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022]
Abstract
The properties and functions of BMSCs were altered by the diabetic microenvironment, and its mechanism was not very clear. In recent years, the regulation of the function of BMSCs by microRNA has become a research hotspot, meanwhile, HOX genes also have been focused on and involved in multiple functions of stem cells. In this study, we investigated the role of miR-139-5p in diabetes-induced BMSC impairment. Since HOXA9 may be a target gene of miR-139-5p, we speculated that miR-139-5p/HOXA9 might be involved in regulating the biological characteristics and the function of BMSCs in diabetes. We demonstrated that the miR-139-5p expression was increased in BMSCs derived from STZ-induced diabetic rats. MiR-139-5p mimics were able to inhibit cell proliferation, and migration and promoted senescence and apoptosis in vitro. MiR-139-5p induced the down-regulated expression of HOXA9 and c-Fos in BMSCs derived from normal rats. Moreover, miR-139-5p inhibitors reversed the tendency in diabetic-derived BMSCs. Further, gain-and-loss function experiments indicated that miR-139-5p regulated the functions of BMSCs by targeting HOXA9 and c-Fos. In vivo wound model experiments showed that the downregulation of miR-139-5p further promoted the epithelialization and angiogenesis of diabetic BMSC-mediated skin. In conclusion, induction of miR-139-5p upregulation mediated the impairment of BMSCs through the HOXA9/c-Fos pathway in diabetic rats. Therefore, miR-139-5p/HOXA9 might be an important therapeutic target in treating diabetic BMSCs and diabetic complications in the future.
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Affiliation(s)
- Fang Liang
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, China
| | - Yu-Fang Luo
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, China
| | - Zi Guo
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, China
| | - Qiang Qian
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, China
| | - Xu-Biao Meng
- Department of Endocrinology, Haikou People's Hospital & Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China
| | - Zhao-Hui Mo
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, China
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22
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Wei L, Xu Y, Zhang L, Yang L, Zhao RC, Zhao D. Mesenchymal Stem Cells Promote Wound Healing and Effects on Expression of Matrix Metalloproteinases-8 and 9 in the Wound Tissue of Diabetic Rats. Stem Cells Dev 2023; 32:25-31. [PMID: 36322784 DOI: 10.1089/scd.2021.0218] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Diabetic foot ulcer (DFU) is a multifactorial complication of diabetes, mainly manifested as infection, ulcer, or destruction of deep tissue, and there is currently no effective treatment. Several preclinical and clinical studies have proved that the transplantation of mesenchymal stem cells (MSCs) improved wound healing. In this study, we evaluated the therapeutic efficacy of human umbilical cord (hUC-MSCs) in DFU rat model. One dose of hUC-MSCs (1 × 106 cells) was subcutaneously injected around wounds in male Sprague-Dawley rats. Wound healing was evaluated macroscopically (wound closure) every 3 days. In addition, we measured growth factors and specific proteins [matrix metalloproteinases (MMPs)-9 and MMP-8] on Day 14 post hUC-MSC transplantation. Results showed significant differences in the wound healing kinetics of lesions that received hUC-MSCs compared to lesions that received vehicle (phosphate buffered saline; P < 0.05). Enzyme-linked immunosorbent assay analyses indicated that MMP-9 protein contents were significantly upregulated in DFU animals, while MMP-8 was downregulated compared to the diabetic rats (P < 0.05). After MSC treatment, the level of MMP-9 and MMP-8 decreased and increased compared to the vehicle group, respectively. These findings suggest that hUC-MSC transplantation can ameliorate the healing process of DFU rats and a potential mechanism through which MSCs enhance DFU wound healing by decreasing MMP-9 expression and increasing MMP-8 expression. This study represents a promising opportunity to gain insight into how MSCs mediate wound healing.
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Affiliation(s)
- Lingling Wei
- Center for Endocrine Metabolism and Immune Diseases, Lu He Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Diabetes Research and Care, Beijing, China
| | - Yongsong Xu
- Center for Endocrine Metabolism and Immune Diseases, Lu He Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Diabetes Research and Care, Beijing, China
| | - Lijie Zhang
- Center for Endocrine Metabolism and Immune Diseases, Lu He Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Diabetes Research and Care, Beijing, China
| | - Longyan Yang
- Center for Endocrine Metabolism and Immune Diseases, Lu He Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Diabetes Research and Care, Beijing, China
| | - Robert Chunhua Zhao
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Beijing, China
| | - Dong Zhao
- Center for Endocrine Metabolism and Immune Diseases, Lu He Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Diabetes Research and Care, Beijing, China
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23
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Wang K, Chen Z, Jin L, Zhao L, Meng L, Kong F, He C, Kong F, Zheng L, Liang F. LPS-pretreatment adipose-derived mesenchymal stromal cells promote wound healing in diabetic rats by improving angiogenesis. Injury 2022; 53:3920-3929. [PMID: 36357245 DOI: 10.1016/j.injury.2022.09.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 07/28/2022] [Accepted: 09/23/2022] [Indexed: 02/02/2023]
Abstract
Mesenchymal stem cells (MSCs) play a key role in wound healing, and the advantages of pretreated MSCs in wound healing have previously been reported. In the present study, we investigated the impact of LPS pretreated human adipose-derived MSCs on skin wound healing in diabetic rats. We found that some improvements occurred through improving angiogenesis. Then, we scrutinized the impact of lipopolysaccharide (LPS) treatment on human adipose-derived MSCs in a high-glucose (HG) medium, as an in vitro diabetic model. In vivo findings revealed significant improvements in epithelialization and angiogenesis of diabetic wounds which received LPS pre-MSCs. Particularly, LPS pre-MSCs-treated diabetic wounds reached considerably higher percentages of wound closure. Also, the granulation tissue of these wounds had higher pronounced epithelialization and more vascularization compared with PBS-treated and MSCs-treated diabetic ones by CD31, VEGF, CD90, collagen 1, and collagen 3 immunostaining. Western-blots analyses indicated that LPS pre-MSCs led to the upregulation of vascular endothelial growth factor (VEGF) and DNMT1. In addition, significantly higher cell viability (proliferation/colonie), and elevated VEGF and DNMT1 protein expression were observed when MSCs were treated with LPS (10 ng/ml, 6 h) in HG culture media. Based on these findings, it is suggested that LPS pre-MSCs could promote wound repair and skin regeneration, in some major processes, via the improvement of cellular behaviors of MSCs in the diabetic microenvironment. The beneficial advantages of LPS treated with mesenchymal stem cells on wound healing may lead to establishing a novel approach as an alternative therapeutic procedure to cure chronic wounds in diabetic conditions.
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Affiliation(s)
- Kuixiang Wang
- Department of Orthopaedics, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
| | - Ziying Chen
- Department of Endocrinology, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
| | - Liang Jin
- Department of Hand and Foot Surgery, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
| | - Lili Zhao
- Department of Orthopaedics, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
| | - Libin Meng
- Department of Orthopaedics, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
| | - Fanting Kong
- Department of Oncology Surgery, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
| | - Chenxin He
- Department of Endocrinology, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
| | - Fanlei Kong
- Department of Orthopaedics, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
| | - Lingtao Zheng
- Department of Endocrinology, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
| | - Fang Liang
- Department of Endocrinology, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China.
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24
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Nicolas-Espinosa J, Yepes-Molina L, Carvajal M. Bioactive peptides from broccoli stems strongly enhance regenerative keratinocytes by stimulating controlled proliferation. PHARMACEUTICAL BIOLOGY 2022; 60:235-246. [PMID: 35086428 PMCID: PMC8797740 DOI: 10.1080/13880209.2021.2009522] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 10/28/2021] [Accepted: 11/17/2021] [Indexed: 06/14/2023]
Abstract
CONTEXT As the interest on the research of plant derived bioactive peptides (BPs) for nutraceutical, cosmeceutical and medical applications is increasing, in this work, the application of peptide derived from broccoli to keratinocytes was studied. OBJECTIVE We focussed on the characterization of different peptides hydrolysates from broccoli stems [extracted from total protein (E) and from membrane protein (MF)], and their activity when applied to human keratinocytes. MATERIALS AND METHODS Peptide mixtures from broccoli stems (E and MF) were characterized by proteomics. They were applied to HaCaT cells in order to study cytotoxicity in a concentration range between 20 and 0.15625 µg of protein/mL and wound healing was studied after 24 and 48 h of treatment application. Also, proteomic and gene expression of keratinocytes were analysed. RESULTS Depending on the source, proteins varied in peptide and amino acid composition. An increased proliferation of keratinocytes was shown after the application of the E peptides mixtures, reaching 190% with the lowest concentrations, but enhanced wound healing repair with E and MF appeared, reaching 59% of wound closure after 48 h. At the gene expression and protein levels of keratinocytes, the upregulation of anti-oncogene p53 and keratinization factors were observed. DISCUSSION These results suggest that peptide mixtures obtained from broccoli augmented cell proliferation and prevented the carcinogenic, uncontrolled growth of the cells, with different mechanisms depending on the protein source. CONCLUSIONS The results encourage the opening of new lines of research involving the use of Brassica peptides for pharmaceutic or cosmetic use.
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Affiliation(s)
- Juan Nicolas-Espinosa
- Aquaporins Group, Plant Nutrition Department, Centro de Edafología y Biología Aplicada del Segura (CEBAS-CSIC), Campus Universitario de Espinardo, Murcia, Spain
| | - Lucía Yepes-Molina
- Aquaporins Group, Plant Nutrition Department, Centro de Edafología y Biología Aplicada del Segura (CEBAS-CSIC), Campus Universitario de Espinardo, Murcia, Spain
| | - Micaela Carvajal
- Aquaporins Group, Plant Nutrition Department, Centro de Edafología y Biología Aplicada del Segura (CEBAS-CSIC), Campus Universitario de Espinardo, Murcia, Spain
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25
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Morris ME, Meinsohn MC, Chauvin M, Saatcioglu HD, Kashiwagi A, Sicher NA, Nguyen N, Yuan S, Stavely R, Hyun M, Donahoe PK, Sabatini BL, Pépin D. A single-cell atlas of the cycling murine ovary. eLife 2022; 11:77239. [PMID: 36205477 PMCID: PMC9545525 DOI: 10.7554/elife.77239] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 09/12/2022] [Indexed: 11/13/2022] Open
Abstract
The estrous cycle is regulated by rhythmic endocrine interactions of the nervous and reproductive systems, which coordinate the hormonal and ovulatory functions of the ovary. Folliculogenesis and follicle progression require the orchestrated response of a variety of cell types to allow the maturation of the follicle and its sequela, ovulation, corpus luteum formation, and ovulatory wound repair. Little is known about the cell state dynamics of the ovary during the estrous cycle and the paracrine factors that help coordinate this process. Herein, we used single-cell RNA sequencing to evaluate the transcriptome of >34,000 cells of the adult mouse ovary and describe the transcriptional changes that occur across the normal estrous cycle and other reproductive states to build a comprehensive dynamic atlas of murine ovarian cell types and states.
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Affiliation(s)
- Mary E Morris
- Department of Gynecology and Reproductive Biology, Massachusetts General Hospital, Boston, United States
| | - Marie-Charlotte Meinsohn
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States.,Department of Surgery, Harvard Medical School, Boston, United States
| | - Maeva Chauvin
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States.,Department of Surgery, Harvard Medical School, Boston, United States
| | - Hatice D Saatcioglu
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States.,Department of Surgery, Harvard Medical School, Boston, United States
| | - Aki Kashiwagi
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States.,Department of Surgery, Harvard Medical School, Boston, United States
| | - Natalie A Sicher
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States.,Department of Surgery, Harvard Medical School, Boston, United States
| | - Ngoc Nguyen
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States.,Department of Surgery, Harvard Medical School, Boston, United States
| | - Selena Yuan
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States.,Department of Surgery, Harvard Medical School, Boston, United States
| | - Rhian Stavely
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States.,Department of Surgery, Harvard Medical School, Boston, United States
| | - Minsuk Hyun
- Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, United States
| | - Patricia K Donahoe
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States.,Department of Surgery, Harvard Medical School, Boston, United States
| | - Bernardo L Sabatini
- Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, United States
| | - David Pépin
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States.,Department of Surgery, Harvard Medical School, Boston, United States
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26
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Stelling-Férez J, Gabaldón JA, Nicolás FJ. Oleanolic acid stimulation of cell migration involves a biphasic signaling mechanism. Sci Rep 2022; 12:15065. [PMID: 36064555 PMCID: PMC9445025 DOI: 10.1038/s41598-022-17553-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 07/27/2022] [Indexed: 11/09/2022] Open
Abstract
Cell migration is a critical process for wound healing, a physiological phenomenon needed for proper skin restoration after injury. Wound healing can be compromised under pathological conditions. Natural bioactive terpenoids have shown promising therapeutic properties in wound healing. Oleanolic acid (OA), a triterpenoid, enhances in vitro and in vivo cell migration. However, the underlying signaling mechanisms and pathways triggered by OA are poorly understood. We have previously shown that OA activates epidermal growth factor receptor (EGFR) and downstream effectors such as mitogen-activated protein (MAP) kinase cascade and c-Jun N-terminal kinase (JNK), leading to c-Jun transcription factor phosphorylation, all of which are involved in migration. We performed protein expression or migration front protein subcellular localization assays, which showed that OA induces c-Jun activation and its nuclear translocation, which precisely overlaps at wound-edge cells. Furthermore, c-Jun phosphorylation was independent of EGFR activation. Additionally, OA promoted actin cytoskeleton and focal adhesion (FA) dynamization. In fact, OA induced the recruitment of regulator proteins to FAs to dynamize these structures during migration. Moreover, OA changed paxillin distribution and activated focal adhesion kinase (FAK) at focal adhesions (FAs). The molecular implications of these observations are discussed.
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Affiliation(s)
- Javier Stelling-Férez
- Department of Nutrition and Food Technology, Health Sciences PhD Program, Universidad Católica de Murcia (UCAM), Campus de los Jerónimos nº135, Guadalupe, 30107, Murcia, Spain.,Regeneration, Molecular Oncology and TGF-ß, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain
| | - José Antonio Gabaldón
- Department of Nutrition and Food Technology, Health Sciences PhD Program, Universidad Católica de Murcia (UCAM), Campus de los Jerónimos nº135, Guadalupe, 30107, Murcia, Spain
| | - Francisco José Nicolás
- Regeneration, Molecular Oncology and TGF-ß, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain.
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27
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Luo Y, Liang F, Wan X, Liu S, Fu L, Mo J, Meng X, Mo Z. Hyaluronic Acid Facilitates Angiogenesis of Endothelial Colony Forming Cell Combining With Mesenchymal Stem Cell via CD44/ MicroRNA-139-5p Pathway. Front Bioeng Biotechnol 2022; 10:794037. [PMID: 35350177 PMCID: PMC8957954 DOI: 10.3389/fbioe.2022.794037] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 01/19/2022] [Indexed: 12/13/2022] Open
Abstract
Stem cells and progenitor cells have been identified as potential new therapeutic options for severe limb ischemia to induce angiogenesis, and hyaluronic acid (HA) is commonly applied as a biomaterial in tissue engineering. However, the efficiency of HA combined with human umbilical cord blood-derived endothelial colony forming cells (ECFCs) and human umbilical-derived mesenchymal stem cells (MSCs) on angiogenesis is unclear. In the present study, we showed that HA promoted angiogenesis induced by MSCs-ECFCs in Matrigel plugs and promoted blood perfusion of murine ischemic muscles. Laser confocal microscopy revealed that human-derived cells grew into the host vasculature and formed connections, as shown by mouse-specific CD31+/human-specific CD31+ double staining. In vitro assays revealed that HA supported cell proliferation and migration, enhanced CD44 expression and reduced microRNA (miR)-139-5p expression. Further analysis revealed that miR-139-5p expression was negatively regulated by CD44 in ECFCs. Flow cytometry assays showed that HA increased CD31 positive cells proportion in MSC-ECFC and could be reversed by miR-139-5p mimics transfection. Moreover, the improvement of MSC-ECFC proliferation and migration induced by HA could be blocked by upregulation of miR-139-5p expression. In conclusion, HA facilitates angiogenesis of MSCs-ECFCs, and this positive effect be associated with activation of the CD44/miR-139-5p pathway, providing a promising strategy for improving severe limb ischemia.
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Affiliation(s)
- Yufang Luo
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, China
| | - Fang Liang
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, China
| | - Xinxing Wan
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, China
| | - Shengping Liu
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, China
| | - Lanfang Fu
- Department of Endocrinology, Haikou People’s Hospital and Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China
| | - Jiake Mo
- School of Medicine, Hunan Normal University, Changsha, China
| | - Xubiao Meng
- Department of Endocrinology, Haikou People’s Hospital and Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China
- *Correspondence: Xubiao Meng, ; Zhaohui Mo,
| | - Zhaohui Mo
- Department of Endocrinology, Third Xiangya Hospital of Central South University and Diabetic Foot Research Center of Central South University, Changsha, China
- *Correspondence: Xubiao Meng, ; Zhaohui Mo,
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28
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Yu Q, Qiao GH, Wang M, Yu L, Sun Y, Shi H, Ma TL. Stem Cell-Based Therapy for Diabetic Foot Ulcers. Front Cell Dev Biol 2022; 10:812262. [PMID: 35178389 PMCID: PMC8844366 DOI: 10.3389/fcell.2022.812262] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic foot ulcer has become a worldwide clinical medical challenge as traditional treatments are not effective enough to reduce the amputation rate. Therefore, it is of great social significance to deeply study the pathogenesis and biological characteristics of the diabetic foot, explore new treatment strategies and promote their application. Stem cell-based therapy holds tremendous promise in the field of regenerative medicine, and its mechanisms include promoting angiogenesis, ameliorating neuroischemia and inflammation, and promoting collagen deposition. Studying the specific molecular mechanisms of stem cell therapy for diabetic foot has an important role and practical clinical significance in maximizing the repair properties of stem cells. In addition, effective application modalities are also crucial in order to improve the survival and viability of stem cells at the wound site. In this paper, we reviewed the specific molecular mechanisms of stem cell therapy for diabetic foot and the extended applications of stem cells in recent years, with the aim of contributing to the development of stem cell-based therapy in the repair of diabetic foot ulcers.
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Affiliation(s)
- Qian Yu
- Department of Hepatology, Songjiang Hospital Affiliated to Nanjing Medical University, Shanghai, China
| | - Guo-Hong Qiao
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Min Wang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Li Yu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yaoxiang Sun
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Hui Shi
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China.,Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Tie-Liang Ma
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
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Flores AI, Pipino C, Jerman UD, Liarte S, Gindraux F, Kreft ME, Nicolas FJ, Pandolfi A, Tratnjek L, Giebel B, Pozzobon M, Silini AR, Parolini O, Eissner G, Lang-Olip I. Perinatal derivatives: How to best characterize their multimodal functions in vitro. Part C: Inflammation, angiogenesis, and wound healing. Front Bioeng Biotechnol 2022; 10:965006. [PMID: 35992360 PMCID: PMC9386263 DOI: 10.3389/fbioe.2022.965006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 07/07/2022] [Indexed: 11/13/2022] Open
Abstract
Perinatal derivatives (PnD) are birth-associated tissues, such as placenta, umbilical cord, amniotic and chorionic membrane, and thereof-derived cells as well as secretomes. PnD play an increasing therapeutic role with beneficial effects on the treatment of various diseases. The aim of this review is to elucidate the modes of action of non-hematopoietic PnD on inflammation, angiogenesis and wound healing. We describe the source and type of PnD with a special focus on their effects on inflammation and immune response, on vascular function as well as on cutaneous and oral wound healing, which is a complex process that comprises hemostasis, inflammation, proliferation (including epithelialization, angiogenesis), and remodeling. We further evaluate the different in vitro assays currently used for assessing selected functional and therapeutic PnD properties. This review is a joint effort from the COST SPRINT Action (CA17116) with the intention to promote PnD into the clinics. It is part of a quadrinomial series on functional assays for validation of PnD, spanning biological functions, such as immunomodulation, anti-microbial/anti-cancer activities, anti-inflammation, wound healing, angiogenesis, and regeneration.
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Affiliation(s)
- Ana I. Flores
- Regenerative Medicine Group, Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Caterina Pipino
- Center for Advanced Studies and Technology (CAST), Department of Medical, Oral and Biotechnological Sciences, University G. d’Annunzio Chieti-Pescara, StemTech Group, Chieti, Italy
| | - Urška Dragin Jerman
- University of Ljubljana, Faculty of Medicine, Institute of Cell Biology, Ljubljana, Slovenia
| | - Sergio Liarte
- Laboratorio de Regeneración, Oncología Molecular y TGF-β, IMIB-Arrixaca, Murcia, Spain
- *Correspondence: Günther Eissner, ; Sergio Liarte,
| | - Florelle Gindraux
- Service de Chirurgie Maxillo-Faciale, Stomatologie et Odontologie Hospitalière, CHU Besançon, Besançon, France
- Laboratoire de Nanomédecine, Imagerie, Thérapeutique EA 466, Université Bourgogne Franche-Comté, Besançon, France
| | - Mateja Erdani Kreft
- University of Ljubljana, Faculty of Medicine, Institute of Cell Biology, Ljubljana, Slovenia
| | - Francisco J. Nicolas
- Laboratorio de Regeneración, Oncología Molecular y TGF-β, IMIB-Arrixaca, Murcia, Spain
| | - Assunta Pandolfi
- Center for Advanced Studies and Technology (CAST), Department of Medical, Oral and Biotechnological Sciences, University G. d’Annunzio Chieti-Pescara, StemTech Group, Chieti, Italy
| | - Larisa Tratnjek
- University of Ljubljana, Faculty of Medicine, Institute of Cell Biology, Ljubljana, Slovenia
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Michela Pozzobon
- Department of Women’s and Children’s Health, University of Padova, Padova, Italy and Foundation Institute of Pediatric Research Fondazione Città Della Speranza, Padova, Italy
| | | | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy
| | - Günther Eissner
- Systems Biology Ireland, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
- *Correspondence: Günther Eissner, ; Sergio Liarte,
| | - Ingrid Lang-Olip
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
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Pichlsberger M, Jerman UD, Obradović H, Tratnjek L, Macedo AS, Mendes F, Fonte P, Hoegler A, Sundl M, Fuchs J, Schoeberlein A, Kreft ME, Mojsilović S, Lang-Olip I. Systematic Review of the Application of Perinatal Derivatives in Animal Models on Cutaneous Wound Healing. Front Bioeng Biotechnol 2021; 9:742858. [PMID: 34631683 PMCID: PMC8498585 DOI: 10.3389/fbioe.2021.742858] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/06/2021] [Indexed: 12/21/2022] Open
Abstract
Knowledge of the beneficial effects of perinatal derivatives (PnD) in wound healing goes back to the early 1900s when the human fetal amniotic membrane served as a biological dressing to treat burns and skin ulcerations. Since the twenty-first century, isolated cells from perinatal tissues and their secretomes have gained increasing scientific interest, as they can be obtained non-invasively, have anti-inflammatory, anti-cancer, and anti-fibrotic characteristics, and are immunologically tolerated in vivo. Many studies that apply PnD in pre-clinical cutaneous wound healing models show large variations in the choice of the animal species (e.g., large animals, rodents), the choice of diabetic or non-diabetic animals, the type of injury (full-thickness wounds, burns, radiation-induced wounds, skin flaps), the source and type of PnD (placenta, umbilical cord, fetal membranes, cells, secretomes, tissue extracts), the method of administration (topical application, intradermal/subcutaneous injection, intravenous or intraperitoneal injection, subcutaneous implantation), and the type of delivery systems (e.g., hydrogels, synthetic or natural biomaterials as carriers for transplanted cells, extracts or secretomes). This review provides a comprehensive and integrative overview of the application of PnD in wound healing to assess its efficacy in preclinical animal models. We highlight the advantages and limitations of the most commonly used animal models and evaluate the impact of the type of PnD, the route of administration, and the dose of cells/secretome application in correlation with the wound healing outcome. This review is a collaborative effort from the COST SPRINT Action (CA17116), which broadly aims at approaching consensus for different aspects of PnD research, such as providing inputs for future standards for the preclinical application of PnD in wound healing.
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Affiliation(s)
- Melanie Pichlsberger
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Urška Dragin Jerman
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Hristina Obradović
- Group for Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Larisa Tratnjek
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Ana Sofia Macedo
- LAQV, REQUIMTE, Department of Chemical Sciences-Applied Chemistry Lab, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Francisca Mendes
- iBB-Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB-Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Pedro Fonte
- iBB-Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB-Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Center for Marine Sciences (CCMar), Faculty of Sciences and Technology, University of Algarve, Faro, Portugal.,Department of Chemistry and Pharmacy, Faculty of Sciences and Technology, University of Algarve, Faro, Portugal
| | - Anja Hoegler
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Monika Sundl
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Julia Fuchs
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Andreina Schoeberlein
- Department of Obstetrics and Feto-maternal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Mateja Erdani Kreft
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Slavko Mojsilović
- Group for Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Ingrid Lang-Olip
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
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Burgess JL, Wyant WA, Abdo Abujamra B, Kirsner RS, Jozic I. Diabetic Wound-Healing Science. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:1072. [PMID: 34684109 PMCID: PMC8539411 DOI: 10.3390/medicina57101072] [Citation(s) in RCA: 260] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/28/2021] [Accepted: 10/04/2021] [Indexed: 12/15/2022]
Abstract
Diabetes mellitus is an increasingly prevalent chronic metabolic disease characterized by prolonged hyperglycemia that leads to long-term health consequences. It is estimated that impaired healing of diabetic wounds affects approximately 25% of all patients with diabetes mellitus, often resulting in lower limb amputation, with subsequent high economic and psychosocial costs. The hyperglycemic environment promotes the formation of biofilms and makes diabetic wounds difficult to treat. In this review, we present updates regarding recent advances in our understanding of the pathophysiology of diabetic wounds focusing on impaired angiogenesis, neuropathy, sub-optimal chronic inflammatory response, barrier disruption, and subsequent polymicrobial infection, followed by current and future treatment strategies designed to tackle the various pathologies associated with diabetic wounds. Given the alarming increase in the prevalence of diabetes, and subsequently diabetic wounds, it is imperative that future treatment strategies target multiple causes of impaired healing in diabetic wounds.
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Affiliation(s)
| | | | | | - Robert S. Kirsner
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (J.L.B.); (W.A.W.); (B.A.A.)
| | - Ivan Jozic
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (J.L.B.); (W.A.W.); (B.A.A.)
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Pourmohammadi-Bejarpasi Z, Sabzevari R, Mohammadi Roushandeh A, Ebrahimi A, Mobayen M, Jahanian-Najafabadi A, Darjani A, Habibi Roudkenar M. Combination Therapy of Metadichol Nanogel and Lipocalin-2 Engineered Mesenchymal Stem Cells Improve Wound Healing in Rat Model of Excision Injury. Adv Pharm Bull 2021; 12:550-560. [PMID: 35935055 PMCID: PMC9348536 DOI: 10.34172/apb.2022.059] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/29/2021] [Accepted: 09/11/2021] [Indexed: 11/11/2022] Open
Abstract
Purpose: Currently, several disorders including burns, trauma, excisional and diabetic wounds, and bedsores threaten the human health. Application of mesenchymal stem cells (MSCs) is recommended for treatment of skin disorders. However, because of oxidative stress and inflammation after skin injury, survival of transplanted MSCs is low which in turn negatively affects the efficiency of the MSCs-based therapy. In an attempt to address the aforementioned challenge and introducing a novel potential therapeutic strategy, we employed combination therapy by lipocalin 2 (Lcn2)-engineered MSCs and a Metadichol (an inverse agonist of vitamin D receptor (VDR)) nanogel in a rat model of excisional wound.
Methods: First, human umbilical cord MSCs (hUC-MSCs) was transfected by a recombinant plasmid encoding Lcn2 gene. Next, a combination of Metadichol nanogel and the engineered MSCs was co-applied on wound in rat model of excision injury. Finally the improvement of wound healing in experimental groups was evaluated by photography and histological assessments (hematoxylin and eosin staining).
Results: Our findings revealed that the repair rate was higher in the group received combination therapy comparing to control groups. Notably, Metadichol+Lcn2-MSCs showed significantly higher wound contraction rate compared to control group at all time points (P value < 0.001). Furthermore, wound repair rate was 95% 14 days after surgery, and 100% after 21 days in the treatment groups. Our results also revealed that the combination therapy improved and accelerated the wound healing process.
Conclusion: Our findings suggest a novel potential therapeutic strategy i.e. Lcn2-engineered MSCs and Metadichol for wound healing. However, further preclinical and clinical studies are required.
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Affiliation(s)
| | - Reza Sabzevari
- Medical Biotechnology Department, Paramedicine Faculty, Guilan University of Medical Sciences, Rasht, Iran
| | - Amaneh Mohammadi Roushandeh
- Cellular and Molecular Research Center, Medicine Faculty, Guilan University of Medical Sciences, Rasht, Iran
- Burn and Regenerative Research Center, Medicine Faculty, Guilan University of Medical Sciences, Rasht, Iran
| | - Ammar Ebrahimi
- Medical Biotechnology Department, Paramedicine Faculty, Guilan University of Medical Sciences, Rasht, Iran
| | - Mohammadreza Mobayen
- Burn and Regenerative Research Center, Medicine Faculty, Guilan University of Medical Sciences, Rasht, Iran
| | - Ali Jahanian-Najafabadi
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Abbas Darjani
- Skin Research Center, Department of Dermatology, Razi Hospital, School of Medicine, Guilan University of Medical Science, Rasht, Iran
| | - Mehryar Habibi Roudkenar
- Cellular and Molecular Research Center, Medicine Faculty, Guilan University of Medical Sciences, Rasht, Iran
- Burn and Regenerative Research Center, Medicine Faculty, Guilan University of Medical Sciences, Rasht, Iran
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33
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Hu Y, Lei S, Yan Z, Hu Z, Guo J, Guo H, Sun B, Pan C. Angelica Dahurica Regulated the Polarization of Macrophages and Accelerated Wound Healing in Diabetes: A Network Pharmacology Study and In Vivo Experimental Validation. Front Pharmacol 2021; 12:678713. [PMID: 34234674 PMCID: PMC8256266 DOI: 10.3389/fphar.2021.678713] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/07/2021] [Indexed: 01/22/2023] Open
Abstract
Diabetic wounds exhibit retarded and partial healing processes. Therefore, patients are exposed to an elevated risk of infection. It has been verified that Angelica dahurica (Hoffm.) Benth. and Hook. f. ex Franch. and Sav (A. dahurica) is conducive for wound healing. However, the pharmacological mechanisms of A. dahurica are yet to be established. The present study uses network pharmacology and in vivo experimental validation to investigate the underlying process that makes A. dahurica conducive for faster wound healing in diabetes patients. 54 potential targets in A. dahurica that act on wound healing were identified through network pharmacology assays, such as signal transducer and activator of transcription 3 (STAT3), JUN, interleukin-1β (IL-1β), tumor necrosis factor (TNF), and prostaglandin G/H synthase 2 (PTGS2). Furthermore, in vivo validation showed that A. dahurica accelerated wound healing through anti-inflammatory effects. More specifically, it regulates the polarization of M1 and M2 subtypes of macrophages. A. dahurica exerted a curative effect on diabetic wound healing by regulating the inflammation. Hence, pharmacologic network analysis combined with in vivo validation elucidated the probable effects and underlying mechanisms of A. dahurica's therapeutic effect on diabetic wound healing.
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Affiliation(s)
- Yonghui Hu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Sisi Lei
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Emergency, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhiyue Yan
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Zhibo Hu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Jun Guo
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Hang Guo
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Bei Sun
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Congqing Pan
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
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Study on the Mechanism of Periplaneta americana Extract to Accelerate Wound Healing after Diabetic Anal Fistula Operation Based on Network Pharmacology. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6659154. [PMID: 33777160 PMCID: PMC7969083 DOI: 10.1155/2021/6659154] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 02/15/2021] [Accepted: 02/25/2021] [Indexed: 11/28/2022]
Abstract
Objective Using network pharmacology research methods to explore the healing mechanism of American cockroach extract to accelerate wound healing after diabetic anal fistula surgery. Method The main chemical constituents of extracts from Periplaneta americana were collected by literature retrieval. Chemical composition and targets related to diabetic anal fistula wound could be predicted based on PubChem, Swiss Target Prediction, OMIM, and GeneCards databases, and the putative targets of Periplaneta americana extraction (PAE) for diabetic anal fistula wound were obtained by Venn diagram. These common targets were predicted using the String database for protein-protein interaction (PPI) network and then screening key genes through Cytohubba. Meanwhile, the above targets were analyzed using the DAVID database for gene ontology (GO) enrichment analyses and the Kyoto Encyclopedia of Genes and Genomes (KEGG) path enrichment analyses. Results A total of 12 chemical components of PAE were obtained by literature retrieval, and 61 therapeutic targets that may accelerate the healing of diabetic anal fistula wounds were predicted by the database. According to PPI network analysis, PAE accelerates wound healing after diabetic anal fistula surgery which may be related to proteins such as AKT1, VEGFA, EGFR, CASP3, STAT3, MAPK1, TNF, JUN, ESR1, and MMP9. GO analysis results show that targets of PAE to promote wound healing were mainly involved in biological processes such as cell proliferation, macrophage differentiation, angiogenesis, and response to hypoxia. KEGG analysis showed that the target genes were mainly concentrated in the PI3K-Akt signaling pathway, HIF-1 signaling pathway, and estrogen signaling pathway. Conclusion Periplaneta americana extract regulates multiple targets and multiple pathways to promote wound healing after diabetic anal fistula surgery. PI3K-Akt signaling pathway, HIF-1 signaling pathway, and sex hormone signaling pathway may be key pathways in the process of Periplaneta americana extract promoting wound healing.
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35
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Lin W, Li HY, Yang Q, Chen G, Lin S, Liao C, Zhou T. Administration of mesenchymal stem cells in diabetic kidney disease: a systematic review and meta-analysis. Stem Cell Res Ther 2021; 12:43. [PMID: 33413678 PMCID: PMC7792034 DOI: 10.1186/s13287-020-02108-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/17/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSC) therapy shows great promise for diabetic kidney disease (DKD) patients. Research has been carried out on this topic in recent years. The main goals of this paper are to evaluate the therapeutic effects of MSCs on DKD through a meta-analysis and address the mechanism through a systematic review of the literature. METHOD An electronic search of the Embase, Cochrane Library, ISI Web of Science, PubMed, and US National Library of Medicine (NLM) databases was performed for all articles about MSC therapy for DKD, without species limitations, up to January 2020. Data were pooled for analysis with Stata SE 12. RESULT The MSC-treated group showed a large and statistically significant hypoglycemic effect at 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, and 6 months. Total hypoglycemic effect was observed (SMD = - 1.954, 95%CI - 2.389 to - 1.519, p < 0.001; I2 = 85.1%). The overall effects on serum creatinine (SCr) and blood urea nitrogen (BUN) were analyzed, suggesting that MSC decreased SCr and BUN and mitigated the impairment of renal function (SCr: SMD = - 4.838, 95%CI - 6.789 to - 2.887, p < 0.001; I2 = 90.8%; BUN: SMD = - 4.912, 95%CI - 6.402 to - 3.422, p < 0.001; I2 = 89.3%). Furthermore, MSC therapy decreased the excretion of urinary albumin. Fibrosis indicators were assessed, and the results showed that transforming growth factor-β, collagen I, fibronectin, and α-smooth muscle actin were significantly decreased in the MSC-treated group compared to the control group. CONCLUSION MSCs might improve glycemic control and reduce SCr, BUN, and urinary protein. MSCs can also alleviate renal fibrosis. MSC therapy might be a potential treatment for DKD.
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Affiliation(s)
- Wenshan Lin
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Hong-Yan Li
- Department of Nephrology, Huadu District People's Hospital of Guangzhou, Southern Medical University, Guangzhou, China
| | - Qian Yang
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Guangyong Chen
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Shujun Lin
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Chunling Liao
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Tianbiao Zhou
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China.
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Xie Q, Liu R, Jiang J, Peng J, Yang C, Zhang W, Wang S, Song J. What is the impact of human umbilical cord mesenchymal stem cell transplantation on clinical treatment? Stem Cell Res Ther 2020; 11:519. [PMID: 33261658 PMCID: PMC7705855 DOI: 10.1186/s13287-020-02011-z] [Citation(s) in RCA: 134] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 11/03/2020] [Indexed: 12/13/2022] Open
Abstract
Background Human umbilical cord mesenchymal stem cells (HUC-MSCs) present in the umbilical cord tissue are self-renewing and multipotent. They can renew themselves continuously and, under certain conditions, differentiate into one or more cell types constituting human tissues and organs. HUC-MSCs differentiate, among others, into osteoblasts, chondrocytes, and adipocytes and have the ability to secrete cytokines. The possibility of noninvasive harvesting and low immunogenicity of HUC-MSCs give them a unique advantage in clinical applications. In recent years, HUC-MSCs have been widely used in clinical practice, and some progress has been made in their use for therapeutic purposes. Main body This article describes two aspects of the clinical therapeutic effects of HUC-MSCs. On the one hand, it explains the benefits and mechanisms of HUC-MSC treatment in various diseases. On the other hand, it summarizes the results of basic research on HUC-MSCs related to clinical applications. The first part of this review highlights several functions of HUC-MSCs that are critical for their therapeutic properties: differentiation into terminal cells, immune regulation, paracrine effects, anti-inflammatory effects, anti-fibrotic effects, and regulating non-coding RNA. These characteristics of HUC-MSCs are discussed in the context of diabetes and its complications, liver disease, systemic lupus erythematosus, arthritis, brain injury and cerebrovascular diseases, heart diseases, spinal cord injury, respiratory diseases, viral infections, and other diseases. The second part emphasizes the need to establish an HUC-MSC cell bank, discusses tumorigenicity of HUC-MSCs and the characteristics of different in vitro generations of these cells in the treatment of diseases, and provides technical and theoretical support for the clinical applications of HUC-MSCs. Conclusion HUC-MSCs can treat a variety of diseases clinically and have achieved good therapeutic effects, and the development of HUC-MSC assistive technology has laid the foundation for its clinical application.
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Affiliation(s)
- Qixin Xie
- Anhui Key Laboratory, Department of Pharmacy, Yijishan Hospital Affiliated to Wannan Medical College, Wuhu, China
| | - Rui Liu
- Department of Medical Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Jia Jiang
- Anhui Key Laboratory, Department of Pharmacy, Yijishan Hospital Affiliated to Wannan Medical College, Wuhu, China
| | - Jing Peng
- Anhui Key Laboratory, Department of Pharmacy, Yijishan Hospital Affiliated to Wannan Medical College, Wuhu, China
| | - Chunyan Yang
- Anhui Key Laboratory, Department of Pharmacy, Yijishan Hospital Affiliated to Wannan Medical College, Wuhu, China
| | - Wen Zhang
- Anhui Key Laboratory, Department of Pharmacy, Yijishan Hospital Affiliated to Wannan Medical College, Wuhu, China
| | - Sheng Wang
- Anhui Key Laboratory, Department of Pharmacy, Yijishan Hospital Affiliated to Wannan Medical College, Wuhu, China
| | - Jing Song
- Anhui Key Laboratory, Department of Pharmacy, Yijishan Hospital Affiliated to Wannan Medical College, Wuhu, China.
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Yang M, He S, Su Z, Yang Z, Liang X, Wu Y. Thermosensitive Injectable Chitosan/Collagen/β-Glycerophosphate Composite Hydrogels for Enhancing Wound Healing by Encapsulating Mesenchymal Stem Cell Spheroids. ACS OMEGA 2020; 5:21015-21023. [PMID: 32875238 PMCID: PMC7450604 DOI: 10.1021/acsomega.0c02580] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 08/03/2020] [Indexed: 05/15/2023]
Abstract
Chronic wounds caused by diabetic or venous diseases remain a social and healthcare burden. In this work, a new strategy is proposed in which injectable thermosensitive chitosan/collagen/β-glycerophosphate (β-GP) hydrogels were combined with three-dimensional mesenchymal stem cell (3D MSC) spheroids to accelerate chronic wound healing by enhanced vascularization and paracrine effects. Chitosan/collagen/β-GP solution mixed with 3D MSC spheroids was rapidly transformed to a gel at body temperature by physical cross-linking, then overlapped the wounds fully and fitted to any shape of the wound. The results showed that the combination therapy exhibited a markedly therapeutic effect than the hydrogel-loaded two-dimensional (2D) MSCs or 2D MSCs alone. The hydrogel could provide an environment conductive to the attachment and proliferation of encapsulated MSCs, especially accelerating the proliferation and paracrine factor secretion of 3D MSC spheroids. These results supplied a novel alternative approach to treat chronic wounds caused by diabetic or venous diseases.
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Affiliation(s)
- Ming Yang
- X&Y
Industrial Company Limited, Shenzhen 518103, Guangdong, China
- . Tel.: 86 755 27806543. Fax: 86 755 27806543
| | - Shuohai He
- School
of Textile Materials and Engineering, Wuyi
University, Jiangmen 529020, P. R. China.
| | - Ziyue Su
- School
of Textile Materials and Engineering, Wuyi
University, Jiangmen 529020, P. R. China.
| | - Zihang Yang
- School
of Textile Materials and Engineering, Wuyi
University, Jiangmen 529020, P. R. China.
| | - Xinxin Liang
- School
of Textile Materials and Engineering, Wuyi
University, Jiangmen 529020, P. R. China.
| | - Yingzhu Wu
- School
of Textile Materials and Engineering, Wuyi
University, Jiangmen 529020, P. R. China.
- . Tel.: 86 750 3296060. Fax: 86 750 3296066
| |
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