In‐cytoplasm mitochondrial transplantation for mesenchymal stem cells engineering and tissue regeneration

Yao, Xudong; Ma, Yihua; Zhou, Wenyan; Liao, Youguo; Jiang, Zongsheng; Lin, Junxin; He, Qun; Wu, Hongwei; Wei, Wei; Wang, Xiaozhao; Björklund, Mikael; Ouyang, Hongwei

doi:10.1002/btm2.10250

Cited by 19 publications

(12 citation statements)

References 66 publications

(111 reference statements)

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“…Mitochondrial membrane potential (ΔΨm) is commonly used to detect mitochondrial function, with a loss of ΔΨm indicating mitochondrial depolarization. The presence of an electrochemical potential gradient in functional mitochondria drives accumulation of the JC‐1 fluorescent dye in the mitochondrial matrix, forming red fluorescent (JC‐1 aggregates) in healthy cells; while loss of ΔΨm leading to a fluorescence shift to green one (JC‐1 monomers) 42 . Based on this, we found the red/green fluorescence intensity ratio was decreased obviously in alkali‐burned corneal cells compared with the healthy control (Figure S4), indicating the alkali‐burned injury greatly lowered the ΔΨm of corneal cells.…”

Section: Resultsmentioning

confidence: 99%

“…ΔΨm was measured using the sensitive fluorescent probe JC-1, a cationic dye of 5,5 0 ,6,6 0 -tetrachloro1,1 0 ,3,3 0 -tetraethyl benzimidazol carbocyanine iodide. 42 Briefly, the eyes were removed 14 days after treatment, and were immediately frozen in OCT compound (Sakura Finetek). The OCT-embedded slices of the cornea were prepared at 6 μm thickness.…”

Section: Mitochondrial Membrane Potential (δψM) Detectionmentioning

confidence: 99%

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Ferrostatin‐1‐loaded liposome for treatment of corneal alkali burn via targeting ferroptosis

Wang

Jiang

Zhong

et al. 2021

Bioengineering & Transla Med

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Alkali burn is a potentially blinding corneal injury. During the progression of alkali burn‐induced injury, overwhelmed oxidative stress in the cornea triggers cell damage, including oxidative changes in cellular macromolecules and lipid peroxidation in membranes, leading to impaired corneal transparency, decreased vision, or even blindness. In this study, we identified that ferroptosis, a type of lipid peroxidation‐dependent cell death, mediated alkali burn‐induced corneal injury. Ferroptosis‐targeting therapy protected the cornea from cell damage and neovascularization. However, the specific ferroptosis inhibitor ferrostatin‐1 (Fer‐1) is hydrophobic and cannot be directly applied in the clinic. Therefore, we developed Fer‐1‐loaded liposomes (Fer‐1‐NPs) to improve the bioavailability of Fer‐1. Our study demonstrated that Fer‐1‐NPs exerted remarkable curative effects regarding corneal opacity and neovascularization in vivo. The efficacy was comparable to that of dexamethasone, but without appreciable side effects. The significant suppression of ferroptosis (induced by lipid peroxidation and mitochondria disruption), inflammation, and neovascularization might be the mechanisms underlying the therapeutic effect of Fer‐1‐NPs. Moreover, the Fer‐1‐NPs treatment showed no signs of cytotoxicity, hematologic toxicity, or visceral organ damage, which further confirmed the biocompatibility. Overall, Fer‐1‐NPs provide a new prospect for safe and effective therapy for corneal alkali burn.

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Section: Resultsmentioning

confidence: 99%

Section: Mitochondrial Membrane Potential (δψM) Detectionmentioning

confidence: 99%

Ferrostatin‐1‐loaded liposome for treatment of corneal alkali burn via targeting ferroptosis

Wang

Jiang

Zhong

et al. 2021

Bioengineering & Transla Med

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“…Mitochondrial transfer leads to a dramatic enhancement of the bioenergetics, which further leads to changes in the secretome characteristics of ADSCs. The increased production of ATP and increased expression of cyclin-dependent kinases 1 and 2 may contribute to enhanced proliferation, migration, and differentiation abilities of ADSCs in vitro [ 29 ]. Taken together, mitochondrial transplantation is a promising approach to engineering stem cells for tissue regeneration [ 66 , 67 ].…”

Section: Discussionmentioning

confidence: 99%

“…Stem cells for treatment must be appropriately adapted to the harsh in vivo environment [ 28 ]. The transfer of exogenous mitochondria to adipose-derived mesenchymal stem cells (ADSCs) can effectively improve ADSC energy levels, thus achieving effective cell implantation [ 29 ]. Therefore, we hypothesized that exogenous mitochondria could be transferred to BA-MSCs damaged by chemotherapy drug 5-fluorouracil (5-FU) to repair chemotherapy-induced cell damage.…”

Section: Introductionmentioning

confidence: 99%

Platelet-Derived Mitochondria Attenuate 5-FU-Induced Injury to Bone-Associated Mesenchymal Stem Cells

Chen

Liu

Zhang

et al. 2023

Stem Cells International

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Background. Myelosuppression is a common condition during chemotherapy. Bone-associated mesenchymal stem cells (BA-MSCs) play an essential role in the composition of the hematopoietic microenvironment and support hematopoietic activity. However, chemotherapy-induced damage to BA-MSCs is rarely studied. Recent studies have shown that platelets promote the wound-healing capability of MSCs by mitochondrial transfer. Therefore, this study is aimed at investigating the chemotherapy-induced damage to BA-MSCs and the therapeutic effect of platelet-derived mitochondria. Material/Methods. We established in vivo and in vitro BA-MSC chemotherapy injury models using the chemotherapy agent 5-fluorouracil (5-FU). Changes in the mitochondrial dynamics were detected by transmission electron microscopy, and the expression of mitochondrial fusion and fission genes was analyzed by qRT-PCR. In addition, mitochondrial functions were also explored by flow cytometry and luminometer. Platelet-derived mitochondria were incubated with 5-FU-damaged BA-MSCs to repair the injury, and BA-MSC functional changes were examined to assess the therapy efficacy. The mechanism of treatment was explored by studying the expression of mitochondrial fission and fusion genes and hematopoietic regulatory factor genes in BA-MSCs. Results. Stimulation with 5-FU increased the apoptosis and suppressed cell cycle progression of BA-MSCs both in vivo and in vitro. In addition, 5-FU chemotherapy inhibited the hematopoietic regulatory ability and disrupted the mitochondrial dynamics and functions of BA-MSCs. The mitochondrial membrane potential and ATP content of 5-FU-injured BA-MSCs were decreased. Interestingly, when platelet-derived mitochondria were transferred to BA-MSCs, the 5-FU-induced apoptosis was alleviated, and the hematopoietic regulatory ability of 5-FU-injured BA-MSCs was effectively improved by upregulating the expression of mitochondrial fusion genes and hematopoietic regulatory factor genes. Conclusion. BA-MSCs were severely damaged by 5-FU chemotherapy both in vivo and in vitro. Meanwhile, platelet-derived mitochondria could attenuate the 5-FU-induced injury to BA-MSCs, which provides future research directions for exploring the treatment strategies for chemotherapy-injured BA-MSCs and establishes a research basis for related fields.

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“…Rat full-thickness skin defects model Full-thickness wounds were created in male Sprague Dawley rats (200~220g) according to the previous report (110). The animal experiment protocol was approved by the Animal Experimental Ethical Inspection Committee of Southeast University (20211101001).…”

Section: Immunofluorescence (If) Stainingmentioning

confidence: 99%

Multiomics reveal that silk fibroin and sericin differentially potentiate the paracrine functions of mesenchymal stem cells and enhance tissue regeneration

Zhang

Sheng

Chen

et al. 2022

Preprint

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Silk fibroin (SF) and sericin (SS), the two major proteins of silk, are attractive biomaterials that show great potential in regenerative medicine. However, their biochemical interactions with stem cells were not fully understood. Here, we employed multiomics to obtain a global view of the triggered cellular processes and pathways of MSCs by SF and SS. Integrated RNA-seq and proteomics revealed that SF and SS strongly enhanced the paracrine activity of MSCs through differentially activating integrin and glycolytic pathways, rather than directly regulating stem cell fate to initiate multiple but distinct biological processes in MSCs. Those specific paracrine signals of MSCs stimulated by SF and SS effectively promoted skin wound healing by influencing the behaviors of multiple resident cells in skin wound microenvironments. This study provides comprehensive and reliable insights into the cellular interactions with SF and SS, enabling future development of silk-based therapeutics for tissue engineering and stem cell therapy.

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In‐cytoplasm mitochondrial transplantation for mesenchymal stem cells engineering and tissue regeneration

Abstract: Increased ATP promoted cyclin-dependent kinase (CDK) 1 and 2 expression of MSCs to modulate cell cycle progression  Elevated bioenergetics further altered MSCs secretomes  In-cytoplasm mitochondrial transplantation improved MSCs function in culture and in vivo

Cited by 19 publications

References 66 publications

Ferrostatin‐1‐loaded liposome for treatment of corneal alkali burn via targeting ferroptosis

Ferrostatin‐1‐loaded liposome for treatment of corneal alkali burn via targeting ferroptosis

Platelet-Derived Mitochondria Attenuate 5-FU-Induced Injury to Bone-Associated Mesenchymal Stem Cells

Multiomics reveal that silk fibroin and sericin differentially potentiate the paracrine functions of mesenchymal stem cells and enhance tissue regeneration

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