Horizontal mitochondrial transfer and mitochondrial transplantation in skin: protection against UVR-induced ROS damage and enhancement of cell proliferation and wound healing

Journal of Translational Medicine

卷:24

Research

Andrés Caicedo^1,2,3,4,5  Abigail Benavides-Almeida^1,2,3  Sebastián Peñaherrera^1,6  Paola Robayo^1,2,3  Andrés Villagómez^7,8  Matheo León^7,2,3  Andrés Suárez-Usbeck^7,2,3  Santiago D. Padilla-Sánchez^7,9  Martin Santacruz^1,2,3  Tatiana Borja¹⁰  María Belén Arteaga^11,1,2,3  Alissen Haro-Vinueza^1,2,12,3  Gilberto Segnini⁷  Patricia Pontón¹⁰  Fernando Torres^1,2,3  Gustavo Donoso⁷  Daniela Suquillo^1,2,3,6  Lucas Ferreira dos Santos¹³  Pamela Arizo^7,2,3  Domenica Tenesaca^1,2,3  Barbara Antilef¹⁴  Gabriela Zavala^15,16  Diego Barba^1,2,3  Luciano Ferrada^14,17  Andrea del Campo¹⁸  Kevin Zambrano^1,2,3,19,20  Sebastian Chile-Miranda^1,2,3  Cynthia Viera-Catota^1,2,3,6  Solange Cisterna¹⁴  Diego Villavicencio^1,2,3,6  Álvaro A. Pérez-Meza¹  Diego F. Cisneros-Heredia^6,9  Pedro M. Aponte^2,3,7  Francisco Cabrera^2,3,7,9  Patricia Luz-Crawford^3,21,15  Iván M. Moya^3,22  Maria Ines Mitrani³  Maroun Khoury^3,21,15  Estefanía Nova-Lamperti^3,14  Verónica A. Burzio^3,23  Tatiana Maron-Gutierrez^3,13  Ramiro F. Díaz^2,3,7 

[1] Mito-Act Research Consortium, Quito, Ecuador

[2] Universidad San Francisco de Quito USFQ, USFQ Space Front, Quito, Ecuador

[3] AVET S.A.S., Quito, Ecuador

[4] Luvigix, Miami, FL, USA

[5] Department of Anesthesiology, Lehigh Valley Hospital–Cedar Crest, Allentown, USA

[6] Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile

[7] Universidad San Francisco de Quito USFQ, Instituto de Investigaciones en Biomedicina iBiomed, Quito, Ecuador

[8] Molecular and Translational Immunology Laboratory, Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, Universidad de Concepción, Concepción, Chile

[9] Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil

[10] Universidad San Francisco de Quito USFQ, Colegio de Ciencias de la Salud, Escuela de Medicina, Quito, Ecuador

[11] IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile

[12] Center for Integrative Biology, Faculty of Science, Universidad Mayor, 4369, Santiago, Chile

[13] Universidad San Francisco de Quito USFQ, Instituto de Biodiversidad Tropical IBIOTROP, Laboratorio de Salud Animal, Quito, Ecuador

[14] Servicio de Patología, Hospital Vozandes, Quito, Ecuador

[15] Department of Equine Surgery, Regenerative Medicine Lab (VETERM), University of Veterinary Medicine Vienna, Vienna, Austria

[16] Super Space Foods Research Institute, Quito, Ecuador

[17] Universidad San Francisco de Quito USFQ, Colegio de Ciencias Biológicas y Ambientales, Quito, Ecuador

[18] Center for Advanced Microscopy CMA BIOBIO, Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile

[19] Department of Biological Sciences, Faculty of Life Sciences, and Institute of Biomedical Sciences, Faculty of Medicine, Universidad Andrés Bello, Santiago, Chile

[20] Cancer Research Group, Faculty of Engineering and Applied Sciences, Universidad de Las Américas, Quito, Ecuador

[21] Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago, Chile

[22] School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands

[23] Universidad San Francisco de Quito USFQ, Escuela de Medicina Veterinaria, Quito, Ecuador

关键词: Skin;    Mitochondria;    Repair;    Regeneration;    Horizontal Mitochondrial Transplant (HMT);    Artificial Mitochondrial Transfer (AMT);    Mitochondrial Transplant (MT);    Artificial Mitochondrial Transfer/Transplant (AMT/T);    Melanocytes;    Keratinocytes;    Fibroblast;    Ultraviolet Radiation (UVR);    Reactive Oxygen Species (ROS);    Wound Healing;   

DOI  :  10.1186/s12967-026-08801-y

 received in 2026-08-04, accepted in 2026-08-07,  发布年份 2026

来源: Springer

【 摘 要 】

BackgroundSkin homeostasis, protection against ultraviolet radiation (UVR), and wound repair depend on coordinated interactions among melanocytes, keratinocytes, and fibroblasts. Horizontal mitochondrial transfer (HMT) is a naturally occurring form of intercellular communication in which mitochondria move between cells and may contribute to stress adaptation, cellular recovery, and tissue resilience. Artificial mitochondrial transfer (AMT), performed in vitro or ex vivo, and mitochondrial transplantation (MT), involving the direct administration of isolated mitochondria in vivo, seek to therapeutically harness these biological mechanisms. However, HMT among resident skin cells and its relationship to mitochondria-based regenerative strategies remain poorly understood.MethodsHMT among human melanocytes, keratinocytes, and fibroblasts was evaluated under basal conditions and following UVR exposure. Direct 2D coculture and transwell systems were used to assess predominantly contact-dependent and contact-independent HMT, respectively, using fluorescence microscopy. AMT was performed by delivering isolated mitochondria from human fibroblast, human Wharton’s jellymesenchymal stem/stromal cells (WJ-MSCs), or mouse bone marrow MSCs (BM-MSCs) to recipient fibroblasts, followed by assessment of mitochondrial uptake, reactive oxygen species (ROS) production, and cell proliferation. The regenerative effects of locally administered MSC-derived mitochondria were subsequently evaluated in murine and porcine primary-intention wound models: mouse BM-MSC-derived mitochondria were used in murine wounds, whereas human WJ-MSC-derived mitochondria were used in porcine wounds. Outcomes were assessed using histological analysis, the wound healing index (WHI), and, in pigs, spatial quantification of Ki67-positive cells.Results HMT from melanocytes to keratinocytes increased significantly after UVR exposure and occurred predominantly under direct coculture conditions, reaching approximately 39%, compared with less than 9% in transwell assays. HMT in the other donor–recipientcombinationsremainedbelow4%.AMTusing human WJ-MSC-derived mitochondria reduced UVR-induced ROS production, while mitochondria derived from both human WJ-MSCs and mouse BM-MSCs significantly increased fibroblast proliferation, although the magnitude of these effects depended on the mitochondrial dose. In murine wounds, locally administered BM-MSC-derived mitochondria enhanced early histological repair and produced effects comparable to those observed after intact BM-MSC administration. In porcine wounds, WJ-MSC-derived mitochondria increased the WHI, improved collagen-containing tissue organization, and enhanced Ki67 positivity within epidermal and dermal regions directly involved in wound repair.ConclusionsThese findings identify HMT as a cell-type-specific response in the skin, with preferential HMT from melanocytes to keratinocytes that is enhanced by UVR exposure. They also demonstrate that MSC-derived mitochondria can reduce oxidative stress, stimulate fibroblast proliferation, and promote early cutaneous repair after local administration. Together, the results establish a translational link between endogenous mitochondrial exchange and the therapeutic use of AMT and MT, supporting further development of mitochondria-based, cell-free strategies for skin injury and impaired wound healing.

【 授权许可】

CC BY-NC-ND   
© The Author(s) 2026

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