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2000
Volume 20, Issue 7
  • ISSN: 1574-888X
  • E-ISSN: 2212-3946

Abstract

Mesenchymal stem cells (MSCs) are adult stem cells with immunoregulatory abilities and low immunogenicity, exhibiting powerful immunosuppressive effects in various inflammatory diseases and holding promise for therapeutic applications. However, the detailed underlying mechanisms remain unclear. Multiple studies suggest that the immunomodulatory function of MSCs is primarily based on the release of immunoregulatory factors through paracrine effects, contributing to their therapeutic outcomes. Other studies report that the immunosuppressive effects of MSCs are mainly achieved through apoptosis, mitochondrial transfer, and the newly proposed migrasomes, highlighting their potential clinical implications. We propose a novel hypothesis, suggesting that migrasomes released by MSCs play a pivotal role in their immunomodulatory ability, potentially offering new avenues for therapeutic interventions. This article primarily summarizes the possible mechanisms by which MSCs exert their immunomodulatory effects, focusing on MSC apoptosis, mitochondrial transfer, and migrasomes, with implications for developing novel therapeutic strategies.

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2024-09-05
2026-02-05
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References

  1. DingD.C. ShyuW.C. LinS.Z. Mesenchymal stem cells.Cell Transplant.201120151410.3727/096368910X21396235
    [Google Scholar]
  2. GuptaG. HussainM.S. ThapaR. DahiyaR. MahapatraD.K. BhatA.A. SinglaN. SubramaniyanV. RawatS. JakhmolaV. SR. DuaK. Hope on the horizon: Wharton’s jelly mesenchymal stem cells in the fight against COVID-19.Regen. Med.202318967567810.2217/rme‑2023‑007737554111
    [Google Scholar]
  3. HanY. YangJ. FangJ. ZhouY. CandiE. WangJ. HuaD. ShaoC. ShiY. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases.Signal Transduct. Target. Ther.2022719210.1038/s41392‑022‑00932‑035314676
    [Google Scholar]
  4. PredaM.B. NeculachiC.A. FenyoI.M. VacaruA.M. PublikM.A. SimionescuM. BurlacuA. Short lifespan of syngeneic transplanted MSC is a consequence of in vivo apoptosis and immune cell recruitment in mice.Cell Death Dis.202112656610.1038/s41419‑021‑03839‑w34075029
    [Google Scholar]
  5. JiangD. JiangZ. LuD. WangX. LiangH. ZhangJ. MengY. LiY. WuD. HuangY. ChenY. DengH. WuQ. XiongJ. MengA. YuL. Migrasomes provide regional cues for organ morphogenesis during zebrafish gastrulation.Nat. Cell Biol.201921896697710.1038/s41556‑019‑0358‑631371827
    [Google Scholar]
  6. ZhangC. LiT. YinS. GaoM. HeH. LiY. JiangD. ShiM. WangJ. YuL. Monocytes deposit migrasomes to promote embryonic angiogenesis.Nat. Cell Biol.202224121726173810.1038/s41556‑022‑01026‑336443426
    [Google Scholar]
  7. ChengY. RenJ. FanS. WuP. CongW. LinY. LanS. SongS. ShaoB. DaiW. WangX. ZhangH. XuB. LiW. YuanX. HeB. ZhangQ. Nanoparticulates reduce tumor cell migration through affinity interactions with extracellular migrasomes and retraction fibers.Nanoscale Horiz.20227777978910.1039/D2NH00067A35703339
    [Google Scholar]
  8. StrzyzP. Migrasomes promote angiogenesis.Nat. Rev. Mol. Cell Biol.20232428410.1038/s41580‑022‑00570‑y36536115
    [Google Scholar]
  9. PangS.H.M. D’RozarioJ. MendoncaS. BhuvanT. PayneN.L. ZhengD. HisanaA. WallisG. BarugahareA. PowellD. RautelaJ. HuntingtonN.D. DewsonG. HuangD.C.S. GrayD.H.D. HengT.S.P. Mesenchymal stromal cell apoptosis is required for their therapeutic function.Nat. Commun.2021121649510.1038/s41467‑021‑26834‑334764248
    [Google Scholar]
  10. WangJ. CaoZ. WangP. ZhangX. TangJ. HeY. HuangZ. MaoX. ShiS. KouX. Apoptotic extracellular vesicles ameliorate multiple myeloma by restoring fas-mediated apoptosis.ACS Nano2021159143601437210.1021/acsnano.1c0351734506129
    [Google Scholar]
  11. GalleuA. Riffo-VasquezY. TrentoC. LomasC. DolcettiL. CheungT.S. von BoninM. BarbieriL. HalaiK. WardS. WengL. ChakravertyR. LombardiG. WattF.M. OrchardK. MarksD.I. ApperleyJ. BornhauserM. WalczakH. BennettC. DazziF. Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation.Sci. Transl. Med.20179416eaam782810.1126/scitranslmed.aam782829141887
    [Google Scholar]
  12. SegawaK. NagataS. An apoptotic eat me signal: Phosphatidylserine exposure.Trends Cell Biol.2015251163965010.1016/j.tcb.2015.08.00326437594
    [Google Scholar]
  13. NagataS. SuzukiJ. SegawaK. FujiiT. Exposure of phosphatidylserine on the cell surface.Cell Death Differ.201623695296110.1038/cdd.2016.726891692
    [Google Scholar]
  14. HeX. HongW. YangJ. LeiH. LuT. HeC. BiZ. PanX. LiuY. DaiL. WangW. HuangC. DengH. WeiX. Spontaneous apoptosis of cells in therapeutic stem cell preparation exert immunomodulatory effects through release of phosphatidylserine.Signal Transduct. Target. Ther.20216127010.1038/s41392‑021‑00688‑z34262012
    [Google Scholar]
  15. WangR. HaoM. KouX. SuiB. SanmillanM.L. ZhangX. LiuD. TianJ. YuW. ChenC. YangR. SunL. LiuY. GiraudoC. RaoD.A. ShenN. ShiS. Apoptotic vesicles ameliorate lupus and arthritis via phosphatidylserine-mediated modulation of T cell receptor signaling.Bioact. Mater.20232547248410.1016/j.bioactmat.2022.07.02637056273
    [Google Scholar]
  16. BianS.Y. CuiH. ZhangX.N. QiL.P. LiD.Y. Mesenchymal stem cells release membrane microparticles in the process of apoptosis.Zhongguo Shi Yan Xue Ye Xue Za Zhi201220245345722541118
    [Google Scholar]
  17. ZhengC. SuiB. ZhangX. HuJ. ChenJ. LiuJ. WuD. YeQ. XiangL. QiuX. LiuS. DengZ. ZhouJ. LiuS. ShiS. JinY. Apoptotic vesicles restore liver macrophage homeostasis to counteract type 2 diabetes.J. Extracell. Vesicles2021107e1210910.1002/jev2.1210934084287
    [Google Scholar]
  18. LiuJ. QiuX. LvY. ZhengC. DongY. DouG. ZhuB. LiuA. WangW. ZhouJ. LiuS. LiuS. GaoB. JinY. Apoptotic bodies derived from mesenchymal stem cells promote cutaneous wound healing via regulating the functions of macrophages.Stem Cell Res. Ther.202011150710.1186/s13287‑020‑02014‑w33246491
    [Google Scholar]
  19. WynnT.A. VannellaK.M. Macrophages in Tissue Repair, Regeneration, and Fibrosis.Immunity201644345046210.1016/j.immuni.2016.02.01526982353
    [Google Scholar]
  20. HarrellC.R. VolarevicV. Apoptosis: A friend or foe in mesenchymal stem cell-based immunosuppression.Adv. Protein Chem. Struct. Biol.2021126396210.1016/bs.apcsb.2021.01.00234090619
    [Google Scholar]
  21. Scherz-ShouvalR. ElazarZ. ROS, mitochondria and the regulation of autophagy.Trends Cell Biol.200717942242710.1016/j.tcb.2007.07.00917804237
    [Google Scholar]
  22. TanY.L. EngS.P. HafezP. Abdul KarimN. LawJ.X. NgM.H. Mesenchymal stromal cell mitochondrial transfer as a cell rescue strategy in regenerative medicine: A review of evidence in preclinical models.Stem Cells Transl. Med.202211881482710.1093/stcltm/szac04435851922
    [Google Scholar]
  23. PaliwalS. ChaudhuriR. AgrawalA. MohantyS. Human tissue-specific MSCs demonstrate differential mitochondria transfer abilities that may determine their regenerative abilities.Stem Cell Res. Ther.20189129810.1186/s13287‑018‑1012‑030409230
    [Google Scholar]
  24. PittJ.M. KroemerG. ZitvogelL. Extracellular vesicles: Masters of intercellular communication and potential clinical interventions.J. Clin. Invest.201612641139114310.1172/JCI8731627035805
    [Google Scholar]
  25. Díaz-CarballoD. KleinJ. AcikelliA.H. WilkC. SakaS. JastrowH. WennemuthG. DammannP. Giger-PabstU. KhosrawipourV. RassowJ. NienenM. StrumbergD. Cytotoxic stress induces transfer of mitochondria-associated human endogenous retroviral RNA and proteins between cancer cells.Oncotarget2017856959459596410.18632/oncotarget.2160629221178
    [Google Scholar]
  26. LiH. WangC. HeT. ZhaoT. ChenY. ShenY. ZhangX. WangL. Mitochondrial transfer from bone marrow mesenchymal stem cells to motor neurons in spinal cord injury rats via gap junction.Theranostics2019972017203510.7150/thno.2940031037154
    [Google Scholar]
  27. AcquistapaceA. BruT. LesaultP.F. FigeacF. CoudertA.E. le CozO. ChristovC. BaudinX. AuberF. YiouR. Dubois-RandéJ.L. RodriguezA.M. Human mesenchymal stem cells reprogram adult cardiomyocytes toward a progenitor- like state through partial cell fusion and mitochondria transfer.Stem Cells201129581282410.1002/stem.63221433223
    [Google Scholar]
  28. SanchezV. VillalbaN. FioreL. LuzzaniC. MiriukaS. BoverisA. GelpiR.J. BruscoA. PoderosoJ.J. Characterization of tunneling nanotubes in wharton’s jelly mesenchymal stem cells. An intercellular exchange of components between neighboring cells.Stem Cell Rev.201713449149810.1007/s12015‑017‑9730‑828214945
    [Google Scholar]
  29. MorrisonT.J. JacksonM.V. CunninghamE.K. KissenpfennigA. McAuleyD.F. O’KaneC.M. KrasnodembskayaA.D. Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer.Am. J. Respir. Crit. Care Med.2017196101275128610.1164/rccm.201701‑0170OC28598224
    [Google Scholar]
  30. CourtA.C. Le-GattA. Luz-CrawfordP. ParraE. Aliaga-TobarV. BátizL.F. ContrerasR.A. OrtúzarM.I. KurteM. Elizondo-VegaR. Maracaja-CoutinhoV. Pino-LagosK. FigueroaF.E. KhouryM. Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response.EMBO Rep.2020212e4805210.15252/embr.20194805231984629
    [Google Scholar]
  31. EbingerS. ÖzdemirE.Z. ZiegenhainC. TiedtS. Castro AlvesC. GrunertM. DworzakM. LutzC. TuratiV.A. EnverT. HornyH.P. SotlarK. ParekhS. SpiekermannK. HiddemannW. SchepersA. PolzerB. KirschS. HoffmannM. KnappB. HasenauerJ. PfeiferH. Panzer-GrümayerR. EnardW. GiresO. JeremiasI. Characterization of rare, dormant, and therapy-resistant Ccells in acute lymphoblastic leukemia.Cancer Cell201630684986210.1016/j.ccell.2016.11.00227916615
    [Google Scholar]
  32. BurtR. DeyA. ArefS. AguiarM. AkarcaA. BaileyK. DayW. HooperS. KirkwoodA. KirschnerK. LeeS.W. Lo CelsoC. ManjiJ. MansourM.R. MarafiotiT. MitchellR.J. MuirheadR.C. Cheuk Yan NgK. PosporiC. PuccioI. Zuborne-AlapiK. SahaiE. FieldingA.K. Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress.Blood2019134171415142910.1182/blood.201900139831501154
    [Google Scholar]
  33. KoJ.H. KimH.J. JeongH.J. LeeH.J. OhJ.Y. Mesenchymal stem and stromal cells harness macrophage-derived amphiregulin to maintain tissue homeostasis.Cell Rep.2020301138063820.e610.1016/j.celrep.2020.02.06232187551
    [Google Scholar]
  34. YuS. YuL. Migrasome biogenesis and functions.FEBS J.2022289227246725410.1111/febs.1618334492154
    [Google Scholar]
  35. JiaoH. JiangD. HuX. DuW. JiL. YangY. LiX. ShoT. WangX. LiY. WuY.T. WeiY.H. HuX. YuL. Mitocytosis, a migrasome-mediated mitochondrial quality-control process.Cell20211841128962910.e1310.1016/j.cell.2021.04.02734048705
    [Google Scholar]
  36. MaL. LiY. PengJ. WuD. ZhaoX. CuiY. ChenL. YanX. DuY. YuL. Discovery of the migrasome, an organelle mediating release of cytoplasmic contents during cell migration.Cell Res.2015251243810.1038/cr.2014.13525342562
    [Google Scholar]
  37. ZhaoX. LeiY. ZhengJ. PengJ. LiY. YuL. ChenY. Identification of markers for migrasome detection.Cell Discov.2019512710.1038/s41421‑019‑0093‑y31123599
    [Google Scholar]
  38. ZhangY. GuoW. BiM. LiuW. ZhouL. LiuH. YanF. GuanL. ZhangJ. XuJ. Migrasomes: From biogenesis, release, uptake, rupture to homeostasis and diseases.Oxid. Med. Cell. Longev.2022202211310.1155/2022/452577835464764
    [Google Scholar]
  39. QinY. YangJ. LiangC. LiuJ. DengZ. YanB. FuY. LuoY. LiX. WeiX. LiW. Pan-cancer analysis identifies migrasome-related genes as a potential immunotherapeutic target: A bulk omics research and single cell sequencing validation.Front. Immunol.20221399482810.3389/fimmu.2022.99482836405728
    [Google Scholar]
  40. DenizI.A. KarbanováJ. WobusM. BornhäuserM. WimbergerP. KuhlmannJ.D. CorbeilD. Mesenchymal stromal cell-associated migrasomes: a new source of chemoattractant for cells of hematopoietic origin.Cell Commun. Signal.20232113610.1186/s12964‑022‑01028‑636788616
    [Google Scholar]
  41. LiT. SuX. LuP. KangX. HuM. LiC. WangS. LuD. ShenS. HuangH. LiuY. DengX. CaiW. WeiL. LuZ. Bone marrow mesenchymal stem cell-derived dermcidin-containing migrasomes enhance LC3-associated phagocytosis of pulmonary macrophages and protect against post-stroke pneumonia.Adv. Sci. (Weinh.)20231022220643210.1002/advs.20220643237246283
    [Google Scholar]
  42. FerreiraJ.R. TeixeiraG.Q. SantosS.G. BarbosaM.A. Almeida-PoradaG. GonçalvesR.M. Mesenchymal Stromal Cell Secretome: Influencing Therapeutic Potential by Cellular Pre-conditioning.Front. Immunol.20189283710.3389/fimmu.2018.0283730564236
    [Google Scholar]
  43. FanB. LiC. SzaladA. WangL. PanW. ZhangR. ChoppM. ZhangZ.G. LiuX.S. Mesenchymal stromal cell-derived exosomes ameliorate peripheral neuropathy in a mouse model of diabetes.Diabetologia202063243144310.1007/s00125‑019‑05043‑031740984
    [Google Scholar]
  44. KonalaV.B.R. MamidiM.K. BhondeR. DasA.K. PochampallyR. PalR. The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration.Cytotherapy2016181132410.1016/j.jcyt.2015.10.00826631828
    [Google Scholar]
  45. CarusoS. PoonI.K.H. Apoptotic cell-derived extracellular vesicles: More than just debris.Front. Immunol.20189148610.3389/fimmu.2018.0148630002658
    [Google Scholar]
  46. FuY. SuiB. XiangL. YanX. WuD. ShiS. HuX. Emerging understanding of apoptosis in mediating mesenchymal stem cell therapy.Cell Death Dis.202112659610.1038/s41419‑021‑03883‑634108448
    [Google Scholar]
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