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Exosomes From Human Umbilical Cord Stem Cells Suppress Macrophage-to-myofibroblast Transition, Alleviating Renal Fibrosis

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Abstract

Renal fibrosis, a progressive scarring of the kidney, lacks effective treatment. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSC-Exos) hold promise for treating kidney diseases due to their anti-inflammatory properties. This study investigates their potential to lessen renal fibrosis by targeting macrophage-to-myofibroblast transformation (MMT), a key driver of fibrosis. We employed a mouse model of unilateral ureteral obstruction (UUO) and cultured cells exposed to transforming growth factor-β (TGF-β) to mimic MMT. HucMSC-Exos were administered to UUO mice, and their effects on kidney function and fibrosis were assessed. Additionally, RNA sequencing and cellular analysis were performed to elucidate the mechanisms by which HucMSC-Exos inhibit MMT. HucMSC-Exos treatment significantly reduced kidney damage and fibrosis in UUO mice. They downregulated markers of fibrosis (Collagen I, vimentin, alpha-smooth muscle actin) and suppressed MMT (α-SMA + F4/80 + cells). Furthermore, ARNTL, a specific molecule, emerged as a potential target of HucMSC-Exos in hindering MMT and consequently preventing fibrosis. HucMSC-Exos effectively lessen renal fibrosis by suppressing MMT, suggesting a novel therapeutic strategy for managing kidney damage and fibrosis.

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Availability of Data and Materials

The datasets and all the relevant codes are available from the corresponding author.

Abbreviations

HucMSC-Exos:

Human umbilical cord mesenchymal stem cell-derived exosomes

MMT:

Macrophage-to-myofibroblast transformation

UUO:

Unilateral ureteral obstruction

TGF-β:

Transforming growth factor-β

CKD:

Chronic Kidney Disease

ESRD:

End stage renal disease

MSC:

Mesenchymal Stem Cell

HucMSCs:

Human umbilical cord mesenchymal stem cells

TEM:

Transmission Electron Microscope

NTA:

Nanoparticle Tracking Analysis

FBS:

Fetal bovine serum

FACS:

For fluorescence activated cell sorting

FVS:

Fixable Viability Stain

PMSF:

phenylmethylsulfonyl fluoride

PVDF:

polyvinylidene difluoride

ON:

Obstructive Nephropathy

ARNTL:

Aryl Hydrocarbon Receptor Nuclear Translocator Like

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Acknowledgements

The authors thank Chongqing Key Laboratory of Children Urogenital Department and Tissue Engineering and Department of Urology, Children’s Hospital of Chongqing Medical University.

Funding

This work was supported by Chongqing Science and Health Joint TCM Technology Innovation and Application Development Project (2020ZY023877), Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0056), Basic Research and Frontier Exploration Project of Yuzhong District of Chongqing (20200126), the General Basic Research Project from the Ministry of Education Key Laboratory of Child Development and Disorders (GBRP-202109).

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Authors and Affiliations

  1. Department of Urology, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

    Qitong Guo, ** Li, Meiling Chen, Yihang Yu, Yonghong Wan, Zhaoxia Zhang, Chunnian Ren, Lianju Shen, **ng Liu, Dawei He, Guanghui Wei & Deying Zhang

  2. National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, China

    Qitong Guo, ** Li, Meiling Chen, Yihang Yu, Yonghong Wan, Zhaoxia Zhang, Chunnian Ren, Lianju Shen, **ng Liu, Dawei He, Guanghui Wei & Deying Zhang

  3. Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27101, USA

    Yuanyuan Zhang

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  1. Qitong Guo
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Contributions

DZ contributed to the conception and design; QG contributed to the investigation and writing of the original draft; PL, MC,YY and CR contributed to the collection and processing of the data; YW, ZZ, LS and XL provided technological guidance and revised the manuscript critically for important intellectual content; DH, YZ and GW conducted the statistical analysis; All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Deying Zhang.

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All experimental procedures involving animals were conducted in accordance with the Basel Declaration and were approved by the ethics committee of Chongqing Medical University (approval no. CHCMU-IACUC20220429003, approval date 31 March 2022).

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Guo, Q., Li, P., Chen, M. et al. Exosomes From Human Umbilical Cord Stem Cells Suppress Macrophage-to-myofibroblast Transition, Alleviating Renal Fibrosis. Inflammation (2024). https://doi.org/10.1007/s10753-024-02027-0

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