Protective Effect of Mesenchymal Stromal Cells in Diabetic Nephropathy: the In Vitro and In Vivo Role of the M-Sec-tunneling Nanotubes

Overview

Journal Clin Sci (Lond)

Specialties Biochemistry
General Medicine
Science

Date 2024 Nov 13

PMID 39535903

Authors

Federica Barutta

Beatrice Corbetta

Stefania Bellini

Roberto Gambino

Stefania Bruno

Shunsuke Kimura

Koji Hase

Hiroshi Ohno

Gabriella Gruden

Affiliations

Soon will be listed here.

Abstract

Mitochondrial dysfunction plays an important role in the development of podocyte injury in diabetic nephropathy (DN). Tunnelling nanotubes (TNTs) are long channels that connect cells and allow organelle exchange. Mesenchymal stromal cells (MSCs) can transfer mitochondria to other cells through the M-Sec-TNTs system. However, it remains unexplored whether MSCs can form heterotypic TNTs with podocytes, thereby enabling the replacement of diabetes-damaged mitochondria. In this study, we analysed TNT formation, mitochondrial transfer, and markers of cell injury in podocytes that were pre-exposed to diabetes-related insults and then co-cultured with diabetic or non-diabetic MSCs. Furthermore, to assess the in vivo relevance, we treated DN mice with exogenous MSCs, either expressing or lacking M-Sec, carrying fluorescent-tagged mitochondria. MSCs formed heterotypic TNTs with podocytes, allowing mitochondrial transfer, via a M-Sec-dependent mechanism. This ameliorated mitochondrial function, nephrin expression, and reduced apoptosis in recipient podocytes. However, MSCs isolated from diabetic mice failed to confer cytoprotection due to Miro-1 down-regulation. In experimental DN, treatment with exogenous MSCs significantly improved DN, but no benefit was observed in mice treated with MSCs lacking M-Sec. Mitochondrial transfer from exogenous MSCs to podocytes occurred in vivo in a M-Sec-dependent manner. These findings demonstrate that the M-Sec-TNT-mediated transfer of mitochondria from healthy MSCs to diabetes-injured podocytes can ameliorate podocyte damage. Moreover, M-Sec expression in exogenous MSCs is essential for providing renoprotection in vivo in experimental DN.

References

Tseng N, Lambie S, Huynh C, Sanford B, Patel M, Herson P . Mitochondrial transfer from mesenchymal stem cells improves neuronal metabolism after oxidant injury in vitro: The role of Miro1. J Cereb Blood Flow Metab. 2020; 41(4):761-770. PMC: 7983509. DOI: 10.1177/0271678X20928147. View

Kay L, Pienaar I, Cooray R, Black G, Soundararajan M . Understanding Miro GTPases: Implications in the Treatment of Neurodegenerative Disorders. Mol Neurobiol. 2018; 55(9):7352-7365. PMC: 6096957. DOI: 10.1007/s12035-018-0927-x. View

Spees J, Olson S, Whitney M, Prockop D . Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci U S A. 2006; 103(5):1283-8. PMC: 1345715. DOI: 10.1073/pnas.0510511103. View

Rustom A . The missing link: does tunnelling nanotube-based supercellularity provide a new understanding of chronic and lifestyle diseases?. Open Biol. 2016; 6(6). PMC: 4929939. DOI: 10.1098/rsob.160057. View

Cho Y, Kim J, Kim M, Park S, Koh S, Ahn H . Mesenchymal stem cells transfer mitochondria to the cells with virtually no mitochondrial function but not with pathogenic mtDNA mutations. PLoS One. 2012; 7(3):e32778. PMC: 3295770. DOI: 10.1371/journal.pone.0032778. View

Konig T, Nolte H, Aaltonen M, Tatsuta T, Krols M, Stroh T . MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control. Nat Cell Biol. 2021; 23(12):1271-1286. DOI: 10.1038/s41556-021-00798-4. View

Crewe C, Funcke J, Li S, Joffin N, Gliniak C, Ghaben A . Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes. Cell Metab. 2021; 33(9):1853-1868.e11. PMC: 8429176. DOI: 10.1016/j.cmet.2021.08.002. View

Babenko V, Silachev D, Popkov V, Zorova L, Pevzner I, Plotnikov E . Miro1 Enhances Mitochondria Transfer from Multipotent Mesenchymal Stem Cells (MMSC) to Neural Cells and Improves the Efficacy of Cell Recovery. Molecules. 2018; 23(3). PMC: 6017474. DOI: 10.3390/molecules23030687. View

Nagaishi K, Mizue Y, Chikenji T, Otani M, Nakano M, Konari N . Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. Sci Rep. 2016; 6:34842. PMC: 5056395. DOI: 10.1038/srep34842. View

10.

Jiang A, Song A, Zhang C . Modes of podocyte death in diabetic kidney disease: an update. J Nephrol. 2022; 35(6):1571-1584. DOI: 10.1007/s40620-022-01269-1. View

11.

Zhang Y, Yu Z, Jiang D, Liang X, Liao S, Zhang Z . iPSC-MSCs with High Intrinsic MIRO1 and Sensitivity to TNF-α Yield Efficacious Mitochondrial Transfer to Rescue Anthracycline-Induced Cardiomyopathy. Stem Cell Reports. 2016; 7(4):749-763. PMC: 5063626. DOI: 10.1016/j.stemcr.2016.08.009. View

12.

Kretschmer A, Zhang F, Somasekharan S, Tse C, Leachman L, Gleave A . Stress-induced tunneling nanotubes support treatment adaptation in prostate cancer. Sci Rep. 2019; 9(1):7826. PMC: 6534589. DOI: 10.1038/s41598-019-44346-5. View

13.

Gousset K, Marzo L, Commere P, Zurzolo C . Myo10 is a key regulator of TNT formation in neuronal cells. J Cell Sci. 2013; 126(Pt 19):4424-35. DOI: 10.1242/jcs.129239. View

14.

Zurzolo C . Tunneling nanotubes: Reshaping connectivity. Curr Opin Cell Biol. 2021; 71:139-147. DOI: 10.1016/j.ceb.2021.03.003. View

15.

Moschoi R, Imbert V, Nebout M, Chiche J, Mary D, Prebet T . Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy. Blood. 2016; 128(2):253-64. DOI: 10.1182/blood-2015-07-655860. View

16.

Saxena S, Mathur A, Kakkar P . Critical role of mitochondrial dysfunction and impaired mitophagy in diabetic nephropathy. J Cell Physiol. 2019; 234(11):19223-19236. DOI: 10.1002/jcp.28712. View

17.

Wang Y, Cui J, Sun X, Zhang Y . Tunneling-nanotube development in astrocytes depends on p53 activation. Cell Death Differ. 2010; 18(4):732-42. PMC: 3131904. DOI: 10.1038/cdd.2010.147. View

18.

Hanna S, McCoy-Simandle K, Leung E, Genna A, Condeelis J, Cox D . Tunneling nanotubes, a novel mode of tumor cell-macrophage communication in tumor cell invasion. J Cell Sci. 2019; 132(3). PMC: 6382011. DOI: 10.1242/jcs.223321. View

19.

Mittal R, Karhu E, Wang J, Delgado S, Zukerman R, Mittal J . Cell communication by tunneling nanotubes: Implications in disease and therapeutic applications. J Cell Physiol. 2018; 234(2):1130-1146. DOI: 10.1002/jcp.27072. View

20.

Driscoll J, Gondaliya P, Patel T . Tunneling Nanotube-Mediated Communication: A Mechanism of Intercellular Nucleic Acid Transfer. Int J Mol Sci. 2022; 23(10). PMC: 9143920. DOI: 10.3390/ijms23105487. View