Stem Cell-Derived Mitochondria Transplantation: a Novel Strategy and the Challenges for the Treatment of Tissue Injury
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Wang et al. Stem Cell Research & Therapy (2018) 9:106 https://doi.org/10.1186/s13287-018-0832-2 REVIEW Open Access Stem cell-derived mitochondria transplantation: a novel strategy and the challenges for the treatment of tissue injury Jingyu Wang1, Heyangzi Li2, Ying Yao1, Tengfei Zhao3, Ying-ying Chen2, Yue-liang Shen2, Lin-lin Wang2* and Yongjian Zhu1* mammalian cells has been discovered that challenges the Abstract current inheritance of mitochondria and mitochondrial Damage of mitochondria in the initial period of tissue DNA (mtDNA), providing novel thinking for some diseases injury aggravates the severity of injury. Restoration of with mitochondrial damage or defect. The damage of mito- mitochondria dysfunction and mitochondrial-based chondria frequently occurs in the initial period of tissue therapeutics represent a potentially effective therapeutic injury. Release of accumulated ROS, imbalance of calcium strategy. Recently, mitochondrial transfer from stem cells ions,andinsufficientsupplyofenergyareresponsiblefor has been demonstrated to play a significant role in mitochondrial damage, which aggravate cellular apoptosis rescuing injured tissues. The possible mechanisms of and death around the injured region [4–8]. However, mitochondria released from stem cells, the pathways of physiological properties of healthy mitochondria including mitochondria transfer between the donor stem cells and replication, division, fusion, degradation, movement in the recipient cells, and the internalization of mitochondria cytoplasm, and intercellular transfer provide the possibility into recipient cells are discussed. Moreover, a novel of eliminating and replacing the damaged mitochondria [9, strategy for tissue injury based on the concept of stem 10]. Previous published data show that injection of isolated cell-derived mitochondrial transplantation is pointed out, viable respiration-competent myocardial mitochondria into and the advantages and challenges are summarized. the ischemic zone just before reperfusion would reverse postischemic functional deterioration and cellular apoptosis Keywords: Mitochondria, Transfer, Transplantation, and limit infarct size [11]. Thus, replacement of damaged Mesenchymal stem cells, Injury mitochondria may protect cells against further injury. Stem cells including mesenchymal stem cells (MSCs), Background umbilical cord blood stem cells, embryonic stem cells, Mitochondria as the center of cellular metabolism and pro- and induced pluripotent stem cells (IPSCs) with self- duction of energy arose from α-proteobacterium engulfed replication capabilities can differentiate into somatic by a eukaryotic progenitor, consisting of inner and outer cells varying in shape and function [12, 13]. Transplant- membranes that encapsulate the intermembrane space and ation of stem cells recently became a hotspot of research matrix compartments [1]. In mammalian cells, mitochon- to treat tissue injury. Meanwhile, MSCs originating from dria own their special circular and double-stranded the mesoderm are favored in stem cell therapy for four genome, which is evolved from selective mitochondrial reasons: the ability to maintain viability and regenerative ancestor genes [2]. It is theorized that mitochondria in capacity after preservation at −80 °C; simplicity of isola- descendants are exclusively transmitted from their maternal tion and cryopreservation; the ability for rapid replica- individuals [3]. However, mitochondrial transfer between tion and high potential of multilineage differentiation; and minimal or even no immunoreactivity [14, 15]. Scientists are interested in the question of whether * Correspondence: [email protected]; [email protected] MSCs can transfer their mitochondria to somatic cells. 2Department of Basic Medicine Sciences, School of Medicine, Zhejiang University, Hangzhou 310058, China The first report to reveal stem cells as donor cells of 1Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang mitochondria is between MSCs and cancer cells with University School of Medicine, Hangzhou 310009, China impaired mitochondrial respiratory function [16]. Cancer Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wang et al. Stem Cell Research & Therapy (2018) 9:106 Page 2 of 10 cells could accept healthy mitochondria from healthy joints, which results in inflammation and arthritis. Al- cells to increase their invasiveness, tumorigenic poten- though the specific mechanisms remain unclear, tial, and resistance to chemotherapy [17–19]. Thus, inhi- adjusting the immune surveillance mechanisms of biting the process of mitochondrial transfer may play a mtDNA and acquiring intact functional mitochondria vital role in cancer therapy. may promote exogenous mitochondrial donation for Recently, numerous studies have shown that mito- therapeutic purposes. chondrial transfer from stem cells to injured cells has been considered a potential treatment for tissue injury. Mitochondrial transfer in vivo However, the specific mechanisms and critical factors re- Although the phenomenon of mitochondrial transfer in main to be identified. Consequently, in this mini review, cell culture conditions has been widely observed, it is based on the summary of the phenomena of mitochon- necessary to confirm whether mitochondrial transfer can drial transfer between stem cells and various mammalian occur in in-vivo conditions. Recently, evidence indicated cells, we present a novel strategy for tissue injury by that injured neurons are able to capture functional mito- stem cell-derived mitochondrial transplantation, and chondria from astrocytes [33]. CD38/CADPR/Ca2+ the advantages and challenges are summarized. signaling may help astrocytes transfer mitochondria into neurons and promote survival and plasticity. In addition, Mitochondrial transfer in vitro Hayakawa et al. [34] collected extracellular mitochondria Material exchange represents a significant form of inter- particles from primary mouse cortical astrocytes and cellular communication that permits not only transfer of then directly injected them into peri-infarct cortex of small molecules or ions, but also transfer of identified mouse models of focal cerebral ischemia. After 24 h, intracellular structures including lysosomes, endosomal results suggested that transplanted functional mitochon- vesicles, plasma membrane components, and mitochon- dria were indeed present in neurons and cell survival dria in a unidirectional or bidirectional way [20, 21]. It signals were amplified. Furthermore, Yi et al. [35] also has been revealed that mitochondrial transfer can observed mitochondrial transfer during embryonic de- restore the dysfunctional mitochondria in recipient cells, velopment. They collected mitochondria concentrates reprogram the differentiated cells, and even rescue the from murine hepatocytes, and then injected them into injured cells [22–24]. Spees et al. [25] first demonstrated zygotes from older mice. There were better developmen- that after coculture of A549 ρ° cells (lung adenocarcin- tal outcomes in the injected group than in the control oma A549 cell line with defective mtDNA) with MSCs, group, which showed that mitochondrial transfer can A549 ρ° cells could acquire functional mitochondria improve embryonic development. Moreover, replace- from MSCs. Also, the isolated mitochondria from the ment of mitochondria through nuclear transfer among immortalized, untransformed mammary epithelial MCF- oocytes has turned into a research focus recently on the 12A cells could easily enter malignant breast cancer cell strategy for preventing the inheritance of mtDNA lines such as MCF-7, MDA-MB-231, and NCI/ADR-Res diseases [36]. cells rather than entering MSF-12A itself. After mito- Stem cells are recognized as unexceptionable donor chondrial transfer, the proliferation of these cell lines cells for mitochondrial transfer and numerous studies would be suppressed in a dose-dependent pattern, and the have substantiated the significance of mitochondrial sensitivity of MCF-7 cells to doxorubicin, abraxane, and transfer in stem cell therapy, especially MSCs [37]. The carboplatin would be increased [26]. Intriguingly, vascular first evidence for mitochondrial transfer as an in-vivo smooth muscle cells cocultured with MSCs induce upregu- therapeutic tool came from Islam et al.’s study [38]. In lation of proliferation of MSCs through mitochondrial the sepsis acute lung injury (ALI) model (airway-instilled transfer [27]. E. coli LPS in anesthetized mice), bone marrow mesen- Although it has been indicated that isolated mitochon- chymal stem cells (BMSCs) transferred mitochondria to dria transfer to injured cells and replace the damaged or the alveolar epithelium that increased the generation of defective mitochondria to rescue function, the release of ATP and alveolar surfactant that regulates alveolar mitochondria may result in a series of immune responses.