Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritis
Abstract Objective The inflammatory responses from synovial fibroblasts and macrophages and the mitochondrial dysfunction in chondrocytes lead to oxidative stress, disrupt extracellular matrix (ECM) homeostasis, and accelerate the deterioration process of articular cartilage in osteoarthritis (OA)....
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2025-01-01
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| Online Access: | https://doi.org/10.1186/s12967-024-05945-7 |
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| author | Ana Maria Vega-Letter Cynthia García-Guerrero Liliana Yantén-Fuentes Carolina Pradenas Yeimi Herrera-Luna Eliana Lara-Barba Felipe A. Bustamante-Barrientos Masyelly Rojas María Jesús Araya Nicole Jeraldo Constanza Aros Francisca Troncoso Daniela Poblete Angela Court Alexander Ortloff Jose Barraza Francesca Velarde Carlos Farkas Claudio Carril Noymar Luque-Campos Gonzalo Almarza Maximiliano Barahona Jose Matas Lucas Cereceda Rocío Lorca Jorge Toledo Karina Oyarce Rolando Vernal Andrés Caicedo Andrea del Campo Yessia Hidalgo Roberto Elizondo-Vega Farida Djouad Maroun Khoury Fernando E. Figueroa Patricia Luz-Crawford |
| author_facet | Ana Maria Vega-Letter Cynthia García-Guerrero Liliana Yantén-Fuentes Carolina Pradenas Yeimi Herrera-Luna Eliana Lara-Barba Felipe A. Bustamante-Barrientos Masyelly Rojas María Jesús Araya Nicole Jeraldo Constanza Aros Francisca Troncoso Daniela Poblete Angela Court Alexander Ortloff Jose Barraza Francesca Velarde Carlos Farkas Claudio Carril Noymar Luque-Campos Gonzalo Almarza Maximiliano Barahona Jose Matas Lucas Cereceda Rocío Lorca Jorge Toledo Karina Oyarce Rolando Vernal Andrés Caicedo Andrea del Campo Yessia Hidalgo Roberto Elizondo-Vega Farida Djouad Maroun Khoury Fernando E. Figueroa Patricia Luz-Crawford |
| author_sort | Ana Maria Vega-Letter |
| collection | DOAJ |
| description | Abstract Objective The inflammatory responses from synovial fibroblasts and macrophages and the mitochondrial dysfunction in chondrocytes lead to oxidative stress, disrupt extracellular matrix (ECM) homeostasis, and accelerate the deterioration process of articular cartilage in osteoarthritis (OA). In recent years, it has been proposed that mesenchymal stromal cells (MSC) transfer their functional mitochondria to damaged cells in response to cellular stress, becoming one of the mechanisms underpinning their therapeutic effects. Therefore, we hypothesize that a novel cell-free treatment for OA could involve direct mitochondria transplantation, restoring both cellular and mitochondrial homeostasis. Methods Mitochondria were isolated from Umbilical Cord (UC)-MSC (Mito-MSC) and characterized based on their morphology, phenotype, functions, and their ability to be internalized by different articular cells. Furthermore, the transcriptional changes following mitochondrial uptake by chondrocytes were evaluated using an Affymetrix analysis, Lastly, the dose dependence therapeutic efficacy, biodistribution and immunogenicity of Mito-MSC were assessed in vivo, through an intra-articular injection in male C57BL6 mice in a collagenase-induced OA (CIOA) model. Results Our findings demonstrate the functional integrity of Mito-MSC and their ability to be efficiently transferred into chondrocytes, synovial macrophages, and synovial fibroblasts. Moreover, the transcriptomic analysis showed the upregulation of genes involved in stress such as DNA reparative machinery and inflammatory antiviral responses. Finally, Mito-MSC transplantation yielded significant reductions in joint mineralization, a hallmark of OA progression, as well as improvements in OA-related histological signs, with the lower dose exhibiting better therapeutic efficacy. Furthermore, Mito-MSC was detected within the knee joint for up to 24 h post-injection without eliciting an inflammatory response in CIOA mice. Conclusion Collectively, our results reveal that mitochondria derived from MSC are transferred to key articular cells and are retained in the joint without generating an inflammatory immune response mitigating articular cartilage degradation in OA, probably through a restorative effect triggered by the stress antiviral response within OA chondrocytes. |
| format | Article |
| id | doaj-art-40ec04e4b5be4a4dabbd57d49d456932 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-40ec04e4b5be4a4dabbd57d49d4569322025-01-12T12:37:41ZengBMCJournal of Translational Medicine1479-58762025-01-0123111410.1186/s12967-024-05945-7Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritisAna Maria Vega-Letter0Cynthia García-Guerrero1Liliana Yantén-Fuentes2Carolina Pradenas3Yeimi Herrera-Luna4Eliana Lara-Barba5Felipe A. Bustamante-Barrientos6Masyelly Rojas7María Jesús Araya8Nicole Jeraldo9Constanza Aros10Francisca Troncoso11Daniela Poblete12Angela Court13Alexander Ortloff14Jose Barraza15Francesca Velarde16Carlos Farkas17Claudio Carril18Noymar Luque-Campos19Gonzalo Almarza20Maximiliano Barahona21Jose Matas22Lucas Cereceda23Rocío Lorca24Jorge Toledo25Karina Oyarce26Rolando Vernal27Andrés Caicedo28Andrea del Campo29Yessia Hidalgo30Roberto Elizondo-Vega31Farida Djouad32Maroun Khoury33Fernando E. Figueroa34Patricia Luz-Crawford35Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de ValparaísoCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTCentro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de Los AndesCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTFacultad de Odontología, Universidad de ChileCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTDepartamento de Ciencias Veterinarias y Salud Pública, Facultad de Recursos Naturales, Universidad Católica de TemucoDepartamento de Ciencias Veterinarias y Salud Pública, Facultad de Recursos Naturales, Universidad Católica de TemucoCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTLaboratorio de Investigación en Ciencias Biomédicas, Departamento de Ciencias Básicas y Morfología, Facultad de Medicina, Universidad Católica de la Santísima ConcepciónLaboratorio de Neuroinmunología, Facultad de Medicina y Ciencia, Universidad San SebastiánCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTLaboratorio de Fisiología y Bioenergetica Celular, Pontificia Universidad Católica de ChileDepartamento de Ortopedia y Traumatología, Hospital Clinico Universidad de ChileCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTRed de Equipamiento Científico Avanzado-REDECA, Facultad de Medicina, Universidad de ChileLaboratorio de Neuroinmunología, Facultad de Medicina y Ciencia, Universidad San SebastiánFacultad de Odontología, Universidad de ChileUniversidad San Francisco de Quito USFQ, Colegio de Ciencias de la Salud e Instituto de Investigaciones en Biomedicina iBioMed, Escuela de Medicina, Quito, Ecuador-Mito-Act Research ConsortiumLaboratorio de Fisiología y Bioenergetica Celular, Pontificia Universidad Católica de ChileCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTLaboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de ConcepciónIRMB, Université de Montpellier, INSERMCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTCenter of Interventional Medicine for Precision and Advanced Cellular Therapy, IMPACTAbstract Objective The inflammatory responses from synovial fibroblasts and macrophages and the mitochondrial dysfunction in chondrocytes lead to oxidative stress, disrupt extracellular matrix (ECM) homeostasis, and accelerate the deterioration process of articular cartilage in osteoarthritis (OA). In recent years, it has been proposed that mesenchymal stromal cells (MSC) transfer their functional mitochondria to damaged cells in response to cellular stress, becoming one of the mechanisms underpinning their therapeutic effects. Therefore, we hypothesize that a novel cell-free treatment for OA could involve direct mitochondria transplantation, restoring both cellular and mitochondrial homeostasis. Methods Mitochondria were isolated from Umbilical Cord (UC)-MSC (Mito-MSC) and characterized based on their morphology, phenotype, functions, and their ability to be internalized by different articular cells. Furthermore, the transcriptional changes following mitochondrial uptake by chondrocytes were evaluated using an Affymetrix analysis, Lastly, the dose dependence therapeutic efficacy, biodistribution and immunogenicity of Mito-MSC were assessed in vivo, through an intra-articular injection in male C57BL6 mice in a collagenase-induced OA (CIOA) model. Results Our findings demonstrate the functional integrity of Mito-MSC and their ability to be efficiently transferred into chondrocytes, synovial macrophages, and synovial fibroblasts. Moreover, the transcriptomic analysis showed the upregulation of genes involved in stress such as DNA reparative machinery and inflammatory antiviral responses. Finally, Mito-MSC transplantation yielded significant reductions in joint mineralization, a hallmark of OA progression, as well as improvements in OA-related histological signs, with the lower dose exhibiting better therapeutic efficacy. Furthermore, Mito-MSC was detected within the knee joint for up to 24 h post-injection without eliciting an inflammatory response in CIOA mice. Conclusion Collectively, our results reveal that mitochondria derived from MSC are transferred to key articular cells and are retained in the joint without generating an inflammatory immune response mitigating articular cartilage degradation in OA, probably through a restorative effect triggered by the stress antiviral response within OA chondrocytes.https://doi.org/10.1186/s12967-024-05945-7Mitochondria transplantationMesenchymal stromal cellsOsteoarthritisMurine OA modelBiodistributionImmuno-safety |
| spellingShingle | Ana Maria Vega-Letter Cynthia García-Guerrero Liliana Yantén-Fuentes Carolina Pradenas Yeimi Herrera-Luna Eliana Lara-Barba Felipe A. Bustamante-Barrientos Masyelly Rojas María Jesús Araya Nicole Jeraldo Constanza Aros Francisca Troncoso Daniela Poblete Angela Court Alexander Ortloff Jose Barraza Francesca Velarde Carlos Farkas Claudio Carril Noymar Luque-Campos Gonzalo Almarza Maximiliano Barahona Jose Matas Lucas Cereceda Rocío Lorca Jorge Toledo Karina Oyarce Rolando Vernal Andrés Caicedo Andrea del Campo Yessia Hidalgo Roberto Elizondo-Vega Farida Djouad Maroun Khoury Fernando E. Figueroa Patricia Luz-Crawford Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritis Journal of Translational Medicine Mitochondria transplantation Mesenchymal stromal cells Osteoarthritis Murine OA model Biodistribution Immuno-safety |
| title | Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritis |
| title_full | Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritis |
| title_fullStr | Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritis |
| title_full_unstemmed | Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritis |
| title_short | Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritis |
| title_sort | safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell free therapy for osteoarthritis |
| topic | Mitochondria transplantation Mesenchymal stromal cells Osteoarthritis Murine OA model Biodistribution Immuno-safety |
| url | https://doi.org/10.1186/s12967-024-05945-7 |
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