bims-mitrat 2024-03-24 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2024–03–24
nine papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Effects of mitochondrial transplantation on chronic pressure wound healing in a human patient.
Mitochondrial tRNASer(UCN) mutations associated non-syndromic sensorineural hearing loss in Chinese families.
Detection of Nanoparticle-Mediated Change in Mitochondrial Membrane Potential in T Cells Using JC-1 Dye.
Si-Wu-Tang attenuates hepatocyte PANoptosis and M1 polarization of macrophages in non-alcoholic fatty liver disease by influencing the intercellular transfer of mtDNA.
Platelet Concentrates Preconditioning of Mesenchymal Stem Cells and Combined Therapies: Integrating Regenerative Strategies for Enhanced Clinical Applications.
Exosomes derived from umbilical cord-mesenchymal stem cells inhibit the NF-κB/MAPK signaling pathway and reduce the inflammatory response to promote recovery from spinal cord injury.
Combination Therapy of Bone Marrow Mesenchymal Stem Cell Transplantation and Electroacupuncture for the Repair of Intrauterine Adhesions in Rats: Mechanisms and Functional Recovery.
A Selective-Tumor-Penetrating Strategy via Unidirectional Direct Transfer for Intravesical Therapy of Bladder Cancer.
Endovascular transplantation of mRNA-enhanced mesenchymal stromal cells results in superior therapeutic protein expression in swine heart.

Cytotherapy. 2024 Mar 04. pii: S1465-3249(24)00087-2. [Epub ahead of print]

Effects of mitochondrial transplantation on chronic pressure wound healing in a human patient.

Omer Faruk Taner, Oner Ulger, Simay Ersahin, Nesrin Tan Baser, Onur Genc, Gokhan Burcin Kubat.

   BACKGROUND AIMS: Wound healing is a multistage process that requires a concerted effort of various cell types. The intricate processes involved in the healing of wounds result in high energy requirements. Furthermore, mitochondria play a crucial role in the healing process because of their involvement in neo angiogenesis, growth factor synthesis, and cell differentiation. It is unclear how mitochondria transplantation, a promising new approach, influences wound healing.
METHODS: In this study, healthy autologous mitochondria obtained from skeletal muscle were injected into chronic pressure wounds as an intervention to promote wound healing.
RESULTS: Mitochondrial transplantation accelerated wound healing by reducing wound size, increasing granulation tissue, and hastening epithelialization.
CONCLUSIONS: This study is the first to demonstrate the therapeutic efficacy of mitochondrial transplantation in wound healing.

Keywords:  chronic wounds; mitochondrial transplantation; skeletal muscle; wound healing

DOI:  https://doi.org/10.1016/j.jcyt.2024.02.027
Heliyon. 2024 Mar 30. 10(6): e27041

Mitochondrial tRNASer(UCN) mutations associated non-syndromic sensorineural hearing loss in Chinese families.

Dejun Zhang, Jie Wu, Yongyi Yuan, Xiaohong Li, Xue Gao, Dongyang Kang, Xin Zhang, Sha-Sha Huang, Pu Dai.

  Mitochondrial transfer RNA mutation is one of the most important causes of hereditary hearing loss in humans. Mitochondrial transfer RNASer (UCN) gene is another hot spot for mutations associated with non-syndromic hearing loss, besides the 12S ribosomal RNA gene. In this study, we assessed the clinical phenotype and the molecular characteristics of two Chinese families with non-syndromic hearing loss. Mutational analysis revealed that 7445A > G and 7510T > C mutations in the mitochondrial transfer RNASer (UCN) gene were the molecular etiology of Family 1 and Family 2, respectively. However, the clinical and genetic characteristics of the two families carrying the above mutations in the transfer RNASer (UCN) gene exhibited a variable expression of hearing loss and an incomplete penetrance. Sequencing analysis of the complete mitochondrial genome showed the presence of transfer RNATrp 5568A > G and NADH-ubiquinone oxidoreductase chain 4 11696G > A mutations in Family 1. The mitochondrial haplotype analysis showed that the two families belonged to Asian D4 and M80'D haplotypes, respectively, and no pathogenic variations were found in the nuclear genes. To our knowledge, our study is the first to report 7445A > G and 7510T > C mutations in the mitochondrial transfer RNASer (UCN) gene, in multi-generation non-syndromic hearing loss pedigrees from China. Our study suggests that 5568A > G and 11696G > A mutations may enhance the penetrance of hearing loss in Chinese Family 1, while mitochondrial haplotypes and known nuclear genes may not be modifiers for the phenotypic expression of 7445A > G and 7510T > C mutations in these Chinese families.

Keywords:  Hearing loss; Mitochondria; Non-syndromic; Transfer RNA; Transfer RNASer(UCN)

DOI:  https://doi.org/10.1016/j.heliyon.2024.e27041
Methods Mol Biol. 2024 ;2789 153-159

Detection of Nanoparticle-Mediated Change in Mitochondrial Membrane Potential in T Cells Using JC-1 Dye.

Ankit Shah, Marina A Dobrovolskaia.

  Alterations in mitochondrial membrane potential are associated with the generation of reactive oxygen species and cell death. While eliminating cancer cells is beneficial for cancer therapy, cytotoxicity to healthy cells may limit the therapeutic applications of mitochondria-damaging nanoparticles. Due to the critical role mitochondria play in cell viability and function, it is important to detect such alterations when studying nanomaterials for therapeutic applications. The protocol described herein utilizes JC-1 dye to detect nanoparticle-mediated changes in mitochondrial membrane potential and is intended to support mechanistic immunotoxicology studies.

Keywords:  Membrane potential; Mitochondria; Nanoparticles; Oxidative stress; T cells

DOI:  https://doi.org/10.1007/978-1-0716-3786-9_16
J Ethnopharmacol. 2024 Mar 20. pii: S0378-8741(24)00356-8. [Epub ahead of print] 118057

Si-Wu-Tang attenuates hepatocyte PANoptosis and M1 polarization of macrophages in non-alcoholic fatty liver disease by influencing the intercellular transfer of mtDNA.

Zhi Ma, Kaihong Xie, Xiaoyong Xue, Jianan Li, Yang Yang, Jianzhi Wu, Yufei Li, Xiaojiaoyang Li.

   ETHNOPHARMACOLOGICAL RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) represents a burgeoning challenge for public health with potential progression to malignant liver diseases. PANoptosis, an avant-garde conceptualization of cell deaths, is closely associated with mitochondrial damage and linked to multiple liver disorders. Si-Wu-Tang (SWT), a traditional Chinese herbal prescription renowned for regulating blood-related disorders and ameliorating gynecological and hepatic diseases, has been demonstrated to alleviate liver fibrosis by regulating bile acid metabolism and immune responses.
AIM OF THE STUDY: However, the mechanisms by which mtDNA is released from PANoptotic hepatocytes, triggering macrophage activation and hepatitis and whether this process can be reversed by SWT remain unclear.
MATERIALS AND METHODS: Here, sophisticated RNA-sequencing complemented by molecular approaches were applied to explore the underlying mechanism of SWT against NAFLD in methionine/choline-deficient diet (MCD)-induced mice and relative in vitro models.
RESULTS: We revealed that SWT profoundly repaired mitochondrial dysfunction, blocked mitochondrial permeability transition and mtDNA released to the cytoplasm, subsequently reversing hepatocyte PANoptosis and macrophage polarization both in MCD-stimulated mice and in vitro. Mechanically, loaded lipids dramatically promoted the opening of mPTP and oligomerization of VDAC2 to orchestrate mtDNA release, which was combined with ZBP1 to promote hepatocyte PANoptosis and also taken by macrophages to trigger M1 polarization via the FSTL1 and PKM2 combination. SWT effectively blocked NOXA signaling and reversed all these detrimental outcomes.
CONCLUSION: Our findings show that SWT protects against hepatitis-mediated hepatocyte PANoptosis and macrophage M1 polarization by influencing intrahepatic synthesis, release and intercellular transfer of mtDNA, suggesting a potential therapeutic strategy for ameliorating NAFLD.

Keywords:  Macrophage activation; Mitochondrial DNA; Non-alcoholic fatty liver disease; PANoptosis; Si-Wu-Tang

DOI:  https://doi.org/10.1016/j.jep.2024.118057
Cell Transplant. 2024 Jan-Dec;33:33 9636897241235460

Platelet Concentrates Preconditioning of Mesenchymal Stem Cells and Combined Therapies: Integrating Regenerative Strategies for Enhanced Clinical Applications.

Xu-Huan Li, Han-Xi Xiao, Zu-Xiu Wang, Xin-Rong Tang, Xue-Feng Yu, Yong-Ping Pan.

  This article presents a comprehensive review of the factors influencing the efficacy of mesenchymal stem cells (MSCs) transplantation and its association with platelet concentrates (PCs). It focuses on investigating the impact of PCs' composition, the age and health status of platelet donors, application methods, and environmental factors on the outcomes of relevant treatments. In addition, it delves into the strategies and mechanisms for optimizing MSCs transplantation with PCs, encompassing preconditioning and combined therapies. Furthermore, it provides an in-depth exploration of the signaling pathways and proteomic characteristics associated with preconditioning and emphasizes the efficacy and specific effects of combined therapy. The article also introduces the latest advancements in the application of biomaterials for optimizing regenerative medical strategies, stimulating scholarly discourse on this subject. Through this comprehensive review, the primary goal is to facilitate a more profound comprehension of the factors influencing treatment outcomes, as well as the strategies and mechanisms for optimizing MSCs transplantation and the application of biomaterials in regenerative medicine, offering theoretical guidance and practical references for related research and clinical practice.

Keywords:  mesenchymal stem cells; platelet concentrates; regenerative medicine

DOI:  https://doi.org/10.1177/09636897241235460
J Orthop Surg Res. 2024 Mar 16. 19(1): 184

Exosomes derived from umbilical cord-mesenchymal stem cells inhibit the NF-κB/MAPK signaling pathway and reduce the inflammatory response to promote recovery from spinal cord injury.

Zhiwei Luan, Jingsong Liu, Mi Li, Yangyang Wang, Yansong Wang.

  Spinal cord injury (SCI) is a serious traumatic disease of the central nervous system and leads to incomplete or complete loss of the body's autonomous motor and sensory functions, seriously endangering human health. Recently, exosomes have been proposed as important substances in cell-to-cell interactions. Mesenchymal stem cell (MSC)-derived exosomes exert good therapeutic effects and play a crucial role in neurological damage repair. However, the detailed mechanisms underlying their effects remain unknown. Herein, we found that compared to SCI rats, those subjected to umbilical cord MSC (UC-MSC)-derived exosomes injection showed an improved motor ability. Nevertheless, the transcriptome of BV2 microglia in different treatment groups indicated that the action pathway of exosomes might be the NF-κB/MAPK pathway. Additionally, exosomes from UC-MSCs could inhibit P38, JNK, ERK, and P65 phosphorylation in BV2 microglia and SCI rat tissues. Moreover, exosomes could inhibit apoptosis and inflammatory reaction and reactive oxygen species (ROS) production of BV2 microglia in vitro and in vivo. In conclusion, UC-MSCs-derived exosomes might protect SCI in rats by inhibiting inflammatory response via the NF-κB/MAPK signaling pathway, representing novel treatment targets or approaches for SCI.

Keywords:  Exosomes; Inflammation; Sequencing; Spinal cord injury; Transplanted mesenchymal stem cells

DOI:  https://doi.org/10.1186/s13018-024-04651-w
Reprod Sci. 2024 Mar 18.

Combination Therapy of Bone Marrow Mesenchymal Stem Cell Transplantation and Electroacupuncture for the Repair of Intrauterine Adhesions in Rats: Mechanisms and Functional Recovery.

Zhaoxian Wang, Liangjun Xia, Jie Cheng, Jingyu Liu, Qian Zhu, Chuting Cui, Junwei Li, Yueying Huang, Jie Shen, Youbing Xia.

  Transplantation of bone marrow mesenchymal stem cells (BMSCs) has demonstrated promising clinical utility in the treatment of endometrial injury and the restoration of fertility. However, since the efficacy of BMSCs after transplantation is not stable, it is very important to find effective ways to enhance the utilisation of BMSCs. Electroacupuncture (EA) has some positive effects on the chemotaxis of stem cells and diseases related to uterine injury. In this study, we established the intrauterine adhesion (IUA) model of the Sprague-Dawley rat using lipopolysaccharide infection and mechanical scratching. Phosphate-buffered saline, BMSCs alone, and BMSCs combined with EA were randomly administered to the rats. Fluorescent cell labelling showed the migration of transplanted BMSCs. H&E staining, Masson staining, Western blot, immunohistochemistry, ELISA, and qRT-PCR were utilised to detect changes in endometrial morphology and expressions of endometrial receptivity-related factors, endometrial pro-inflammatory factors, and fibrosis factors. Finally, we conducted a fertility test to measure the recovery of uterine function. The results showed that EA promoted transplanted BMSCs to migrate into the injured uterus by activating the SDF-1/CXCR4 axis. Endometrial morphology showed the most significant improvement in the BMSC + EA group. The expressions of endometrial pro-inflammatory factors and fibrosis indexes in the BMSC + EA group were lower than those in the model and BMSC groups. Further studies revealed that the expression of endometrial receptivity-related factors and the number of embryos implanted on day 8 of gestation increased in the BMSC + EA group compared with the model group and the BMSC group.

Keywords:  Bone marrow mesenchymal stem cells; Electroacupuncture; Fibrosis; Inflammation; Intrauterine adhesion; Stem cell migration

DOI:  https://doi.org/10.1007/s43032-024-01465-3
J Med Chem. 2024 Mar 18.

A Selective-Tumor-Penetrating Strategy via Unidirectional Direct Transfer for Intravesical Therapy of Bladder Cancer.

Xiaowen Qin, Heng Wang, Wentao Xu, Bin Zheng, Haibao Zhang, Qi Zhang, Yang Liu, Zhenghong Liu, Li Sun, Yixuan Mou, Cenchao Yao, Wei Zheng, Yiyang Chen, Chenkai Wang, Xuanyi Zhou, Youqing Shen, Pu Zhang, Dahong Zhang.

A selective tumor-penetrating strategy generally exploits tumor-targeted ligands to modify drugs so that the conjugate preferentially enters tumors and subsequently undergoes transcellular transport to penetrate tumors. However, this process shields ligands from their corresponding targets on the cell surface, possibly inducing an off-target effect during drug penetration at the tumor-normal interface. Herein, we first describe a selective tumor-penetrating drug (R11-phalloidin conjugates) for intravesical therapy of bladder cancer. The intravesical conjugates rapidly translocated across the mucus layer, specifically bound to tumors, and infiltrated throughout the tumor via direct intercellular transfer. Notably, direct transfer from normal cells to tumor cells was unidirectional because the pathways required for direct transfer, termed F-actin-rich tunneling nanotubes, were more unidirectionally extended from normal cells to tumor cells. Moreover, the intravesical conjugates displayed strong anticancer activity and well-tolerated biosafety in murine orthotopic bladder tumor models. Our study demonstrated the potential of a selective tumor-penetrating conjugate for effective intravesical anticancer therapy.

DOI: https://doi.org/10.1021/acs.jmedchem.4c00060
Mol Ther Methods Clin Dev. 2024 Jun 13. 32(2): 101225

Endovascular transplantation of mRNA-enhanced mesenchymal stromal cells results in superior therapeutic protein expression in swine heart.

Jonathan Al-Saadi, Mathias Waldén, Mikael Sandell, Jesper Sohlmér, Rikard Grankvist, Ida Friberger, Agneta Andersson, Mattias Carlsten, Kenneth Chien, Johan Lundberg, Nevin Witman, Staffan Holmin.

  Heart failure has a poor prognosis and no curative treatment exists. Clinical trials are investigating gene- and cell-based therapies to improve cardiac function. The safe and efficient delivery of these therapies to solid organs is challenging. Herein, we demonstrate the feasibility of using an endovascular intramyocardial delivery approach to safely administer mRNA drug products and perform cell transplantation procedures in swine. Using a trans-vessel wall (TW) device, we delivered chemically modified mRNAs (modRNA) and mRNA-enhanced mesenchymal stromal cells expressing vascular endothelial growth factor A (VEGF-A) directly to the heart. We monitored and mapped the cellular distribution, protein expression, and safety tolerability of such an approach. The delivery of modRNA-enhanced cells via the TW device with different flow rates and cell concentrations marginally affect cell viability and protein expression in situ. Implanted cells were found within the myocardium for at least 3 days following administration, without the use of immunomodulation and minimal impact on tissue integrity. Finally, we could increase the protein expression of VEGF-A over 500-fold in the heart using a cell-mediated modRNA delivery system compared with modRNA delivered in saline solution. Ultimately, this method paves the way for future research to pioneer new treatments for cardiac disease.

Keywords:  cardiology; cell transplantation; endovascular intervention; endovascular intramyocardial transplantation; heart failure; mRNA drug products; mesenchymal stromal cells; modRNA; trans-vessel wall device; vascular endothelial growth factor

DOI:  https://doi.org/10.1016/j.omtm.2024.101225