bims-mitrat 2025-05-04 papers

Curr Stem Cell Res Ther. 2025 Apr 25.

Mitochondria Transfer in Mesenchymal Stem Cells: Unraveling the Mechanism and Therapeutic Potential.

Jingyi Chen, Zhilang Xie, Huayin Zhou, Yingxin Ou, Wenwen Tan, Aizhen Zhang, Yuying Li, Xingliang Fan.

Mesenchymal stem cells (MSCs) hold transformative potential in translational medicine due to their versatile differentiation abilities and regenerative properties. Notably, MSCs can transfer mitochondria to unrelated cells through intercellular mitochondrial transfer, offering a groundbreaking approach to halting the progression of mitochondrial diseases and restoring function to cells compromised by mitochondrial dysfunction. Although MSC mitochondrial transfer has demonstrated significant therapeutic promise across a range of diseases, its application in clinical settings remains largely unexplored. This review delves into the novel mechanisms by which MSCs execute mitochondrial transfer, highlighting its profound impact on cellular metabolism, immune modulation, and tissue regeneration. We provide an in-depth analysis of the therapeutic potential of MSC mitochondrial transfer, particularly in treating mitochondrial dysfunction-related diseases and advancing tissue repair strategies. Additionally, we propose innovative considerations for optimizing MSC mitochondrial transfer in clinical trials, emphasizing its potential to reshape the landscape of regenerative medicine and therapeutic interventions.

Keywords: Mesenchymal stem cells; immunomodulation; mitochondrial transfer; oxidative stress; therapeutic potential.

DOI: https://doi.org/10.2174/011574888X362739250416153254

Biomater Transl. 2025 ;6(1): 4-23

Recent advances in mitochondrial transplantation to treat disease.

Xiangling Li, Yanjun Guan, Chaochao Li, Haofeng Cheng, Jun Bai, Jinjuan Zhao, Yu Wang, Jiang Peng.

Mitochondrial transplantation (MT), an innovative regenerative technique widely used to treat diseases caused by mitochondrial dysfunction, shows great promise for clinical application. This procedure can increase the number of mitochondria and improve the function of damaged mitochondria, resulting in increased adenosine triphosphate levels, decreased reactive oxygen species production, improved Ca2+ buffering capacity, modulated inflammatory response, and reduced apoptosis to protect cells, thus promoting tissue repair. In this review, we describe research advances in MT over the last five years, focusing on its application in treating various diseases, including ischaemic injuries (of the kidney, heart, lung, and liver), neurodegenerative disorders, spinal cord injury, sepsis, diabetes mellitus, stroke, and ultraviolet radiation injuries, as well as in procedures such as organ transplantation, focusing on instances where MT demonstrated good efficacy. We also cover the application of engineered mitochondria and mitochondrial combination therapies and present the latest advances in improving MT efficiency, as well as the current clinical applications and shortcomings of MT, aiming to provide a theoretical foundation for enhanced MT utilisation in the future.

Keywords: cardiovascular diseases; ischaemia/reperfusion injury; mitochondrial dysfunction; mitochondrial transplantation; neurodegenerative diseases

DOI: https://doi.org/10.12336/biomatertransl.2025.01.002

Biomedicines. 2025 Apr 10. pii: 934. [Epub ahead of print]13(4):

Enhancing Mitochondrial Function Through Pharmacological Modification: A Novel Approach to Mitochondrial Transplantation in a Sepsis Model.

Bomi Kim, Yun-Seok Kim, Kyuseok Kim.

Background/Objectives: Sepsis continues to be a significant global health issue, with current treatments primarily focused on antibiotics, fluid resuscitation, vasopressors, or steroids. Recent studies have started to explore mitochondrial transplantation as a potential treatment for sepsis. This study aims to evaluate the effects of enhanced mitochondrial transplantation on sepsis. Methods: We examined various mitochondrial-targeting drugs (formoterol, metformin, CoQ10, pioglitazone, fenofibrate, and elamipretide) to improve mitochondrial function prior to transplantation. Mitochondrial function was assessed by measuring the oxygen consumption rate (OCR) and analyzing the expression of genes related to mitochondrial biogenesis. Additionally, the effects of enhanced mitochondrial transplantation on inflammation were investigated using an in vitro sepsis model with THP-1 cells. Results: Formoterol significantly increased mitochondrial biogenesis, as evidenced by enhanced oxygen consumption rates and the upregulation of mitochondrial-associated genes, including those related to biogenesis (PGC-1α: 1.56-fold, p < 0.01) and electron transport (mt-Nd6: 1.13-fold, p = 0.16; mt-Cytb: 1.57-fold, p < 0.001; and mt-Co2: 1.44-fold, p < 0.05). Furthermore, formoterol-enhanced mitochondrial transplantation demonstrated a substantial reduction in TNF-α levels in LPS-induced hyperinflammatory THP-1 cells (untreated: 915.91 ± 12.03 vs. formoterol-treated: 529.29 ± 78.23 pg/mL, p < 0.05), suggesting its potential to modulate immune responses. Conclusions: Mitochondrial transplantation using drug-enhancing mitochondrial function might be a promising strategy in sepsis.

Keywords: formoterol; mitochondrial transplantation; proinflammation; sepsis

DOI: https://doi.org/10.3390/biomedicines13040934

Pharmaceutics. 2025 Apr 01. pii: 453. [Epub ahead of print]17(4):

Umbilical Cord Mesenchymal Stem Cell-Derived Apoptotic Extracellular Vesicles Improve 5-FU-Induced Delayed Wound Healing by Mitochondrial Transfer.

Hongbin Lai, Ling Lin, Yanrui Pan, Boqun Wang, Lan Ma, Wei Zhao.

Background/Objectives: This study aimed to explore the therapeutic potential of umbilical mesenchymal stem cell-derived apoptotic vesicles (UMSC-apoVs) in a 5-Fluorouracil (5-FU)-induced impairment in skin wound healing. Methods: UMSC-apoVs were isolated from UMSCs using differential centrifugation after the induction of apoptosis. A murine model was established by administering 5-FU via intravenous tail injection, followed by full-thickness skin wound creation. Mice received local injections of UMSC-apoVs at the lesion site. Wound healing was evaluated based on wound closure rates, histological analysis, and in vivo/in vitro functional assays. Rotenone (Rot)-pretreated UMSC-apoVs were used to explore the role of mitochondrial transfer between skin mesenchymal stem cells (SMSCs) and UMSC-apoVs in wound healing. Results: UMSC-apoVs significantly accelerated wound healing in 5-FU-treated mice, as demonstrated by enhanced wound closure rates and histological findings of reduced inflammatory infiltration and increased collagen deposition. UMSC-apoVs transferred mitochondria to SMSCs, enhancing viability, proliferation, and migration while reducing reactive oxygen species (ROS) production in SMSCs. Rot pretreatment inhibited the therapeutic effects of UMSC-apoVs on wound healing by inducing mitochondrial dysfunction in UMSC-apoVs. Conclusions: Our findings indicate that UMSC-apoVs improve 5-FU-induced impaired skin wound healing by facilitating mitochondrial transfer, suggesting a novel therapeutic strategy for alleviating chemotherapy-induced impairment in wound healing.

Keywords: 5-fluorouracil; delayed wound healing; mitochondrial transfer; skin mesenchymal stem cells; umbilical cord mesenchymal stem cell-derived apoptotic vesicles

DOI: https://doi.org/10.3390/pharmaceutics17040453

Theranostics. 2025 ;15(11): 5499-5517

Nitric oxide-primed engineered extracellular vesicles restore bioenergetics in acute kidney injury via mitochondrial transfer.

Fei Peng, Xiaoniao Chen, Lingling Wu, Jiayi He, Zongjin Li, Quan Hong, Qiang Zhao, Meng Qian, Xu Wang, Wanjun Shen, Tingting Qi, Yiyu Huang, Guangyan Cai, Chuyue Zhang, Xiangmei Chen.

Background: The disruption of mitochondrial homeostasis in acute kidney injury (AKI) is an important factor that drives persistent renal dysfunction. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown great therapeutic potential in AKI, but insufficient specificity of targeting the impaired mitochondrial function. Herein, we developed an engineered nitric oxide (NO)-primed MSC-EVs (pEVs) to restore mitochondrial homeostasis for AKI therapy. Methods: A cisplatin-induced AKI model was established to investigate the therapeutic effects of MSC-EVs. Proteomic and Western blot analyses compared mitochondrial cargos and functional assays included mitochondrial complex I activity and Adenosine triphosphate (ATP) quantification. Mitochondrial transfer was tracked using flow cytometry and confocal imaging. Mitochondrial dynamics, oxidative stress, and apoptosis were evaluated through ATP measurement, western blotting and rotenone-mediated respiratory chain inhibition. Results: Our data indicated that pEVs outperformed cEVs in restoring renal function and histopathology. Additionally, a reduction in mitochondria-associated oxidative stress and cell death was observed. Proteomic profiling revealed that NO priming enriched pEVs with mitochondrial complex I components, which directly enhanced their bioenergetic capacity, as evidenced by higher mitochondrial complex I activity and elevated ATP production compared to cEVs. In vivo tracking confirmed targeted delivery of pEV-derived mitochondrial contents to renal tubular cells, reducing mitochondrial reactive oxygen species (ROS) and restoring mitochondrial mass. Crucially, mitochondria-depleted pEVs abolished these therapeutic effects, establishing mitochondrial cargos as the primary therapeutic driver. Furthermore, pEVs activated a pro-survival cascade in recipient cells, showing superior efficacy in promoting mitochondrial biogenesis, dynamics, and mitophagy, thereby restoring renal mitochondrial homeostasis. Conclusion: Our study elucidated a mitochondria-targeted therapeutic strategy enabled by engineered EVs that deliver functional cargo to restore mitochondrial homeostasis. These advances provide transformative potential for AKI and other mitochondrial disorders.

Keywords: Acute kidney injury.; Extracellular vesicles; Mesenchymal stem cells; Mitochondrial homeostasis; Nitric oxide

DOI: https://doi.org/10.7150/thno.113741