Mesenchymal Stromal Cell-derived Exosomes Ameliorate Peripheral Neuropathy in a Mouse Model of Diabetes

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2019 Nov 20

PMID 31740984

Citations 97

Authors

Baoyan Fan

Chao Li

Alexandra Szalad

Lei Wang

Wanlong Pan

Ruilan Zhang

Michael Chopp

Zheng Gang Zhang

Xian Shuang Liu

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: Diabetic peripheral neuropathy (DPN) is one of the major complications of diabetes, which contributes greatly to morbidity and mortality. There is currently no effective treatment for this disease. Exosomes are cell-derived nanovesicles and play an important role in intercellular communications. The present study investigated whether mesenchymal stromal cell (MSC)-derived exosomes improve neurological outcomes of DPN.

Methods: Exosomes were isolated from the medium of cultured mouse MSCs by ultracentrifugation. Diabetic mice (BKS.Cg-m+/+Lepr/J, db/db) at the age of 20 weeks were used as DPN models. Heterozygous mice (db/m) of the same age were used as the control. MSC-exosomes were administered weekly via the tail vein for 8 weeks. Neurological function was evaluated by testing motor and sensory nerve conduction velocities, and thermal and mechanical sensitivity. Morphometric analysis was performed by myelin sheath staining and immunohistochemistry. Macrophage markers and circulating cytokines were measured by western blot and ELISA. MicroRNA (miRNA) array and bioinformatics analyses were performed to examine the exosomal miRNA profile and miRNA putative target genes involved in DPN.

Results: Treatment of DPN with MSC-exosomes markedly decreased the threshold for thermal and mechanical stimuli and increased nerve conduction velocity in diabetic mice. Histopathological analysis showed that MSC-exosomes markedly augmented the density of FITC-dextran perfused blood vessels and increased the number of intraepidermal nerve fibres (IENFs), myelin thickness and axonal diameters of sciatic nerves. Western blot analysis revealed that MSC-exosome treatment decreased and increased M1 and M2 macrophage phenotype markers, respectively. Moreover, MSC-exosomes substantially suppressed proinflammatory cytokines. Bioinformatics analysis revealed that MSC-exosomes contained abundant miRNAs that target the Toll-like receptor (TLR)4/NF-κB signalling pathway.

Conclusions/interpretation: MSC-derived exosomes alleviate neurovascular dysfunction and improve functional recovery in mice with DPN by suppression of proinflammatory genes.

Citing Articles

SGK1 drives hippocampal demyelination and diabetes-associated cognitive dysfunction in mice.

Jiang Z, Liu B, Lu T, Liu X, Lv R, Yuan K Nat Commun. 2025; 16(1):1709.

PMID: 39962079 PMC: 11833069. DOI: 10.1038/s41467-025-56854-2.

The Role of Inflammation in the Pathogenesis of Diabetic Peripheral Neuropathy: New Lessons from Experimental Studies and Clinical Implications.

Panou T, Gouveri E, Popovic D, Papazoglou D, Papanas N Diabetes Ther. 2025; 16(3):371-411.

PMID: 39928224 PMC: 11868477. DOI: 10.1007/s13300-025-01699-7.

Bridging bioengineering and nanotechnology: Bone marrow derived mesenchymal stem cell-exosome solutions for peripheral nerve injury.

Chang J, Yin X, Zhang M, Liu J, Zhao L World J Stem Cells. 2025; 17(1):101161.

PMID: 39866899 PMC: 11752453. DOI: 10.4252/wjsc.v17.i1.101161.

Network Pharmacology Combined With Metabolomics Reveals the Mechanism of Yangxuerongjin Pill Against Type 2 Diabetic Peripheral Neuropathy in Rats.

Jin R, Pei H, Yue F, Zhang X, Zhang Z, Xu Y Drug Des Devel Ther. 2025; 19():325-347.

PMID: 39834645 PMC: 11745066. DOI: 10.2147/DDDT.S473146.

Keratinocyte-derived extracellular vesicles in painful diabetic neuropathy.

Coy-Dibley J, Jayaraj N, Ren D, Pacifico P, Belmadani A, Wang Y Neurobiol Pain. 2025; 17:100176.

PMID: 39811188 PMC: 11731614. DOI: 10.1016/j.ynpai.2024.100176.

References

Cameron N, EATON S, Cotter M, Tesfaye S . Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia. 2001; 44(11):1973-88. DOI: 10.1007/s001250100001. View

Negi G, Kumar A, Sharma S . Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: effects on NF-κB and Nrf2 cascades. J Pineal Res. 2010; 50(2):124-31. DOI: 10.1111/j.1600-079X.2010.00821.x. View

Toth C, Martinez J, Zochodne D . RAGE, diabetes, and the nervous system. Curr Mol Med. 2008; 7(8):766-76. DOI: 10.2174/156652407783220705. View

Siniscalco D, Giordano C, Galderisi U, Luongo L, Alessio N, Di Bernardo G . Intra-brain microinjection of human mesenchymal stem cells decreases allodynia in neuropathic mice. Cell Mol Life Sci. 2009; 67(4):655-69. PMC: 11115751. DOI: 10.1007/s00018-009-0202-4. View

Peters C, Jimenez-Andrade J, Jonas B, Sevcik M, Koewler N, Ghilardi J . Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells. Exp Neurol. 2006; 203(1):42-54. DOI: 10.1016/j.expneurol.2006.07.022. View

Gong M, Yu B, Wang J, Wang Y, Liu M, Paul C . Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget. 2017; 8(28):45200-45212. PMC: 5542178. DOI: 10.18632/oncotarget.16778. View

Elzinga S, Murdock B, Guo K, Hayes J, Tabbey M, Hur J . Toll-like receptors and inflammation in metabolic neuropathy; a role in early versus late disease?. Exp Neurol. 2019; 320:112967. PMC: 6708507. DOI: 10.1016/j.expneurol.2019.112967. View

Waterman R, Morgenweck J, Nossaman B, Scandurro A, Scandurro S, Betancourt A . Anti-inflammatory mesenchymal stem cells (MSC2) attenuate symptoms of painful diabetic peripheral neuropathy. Stem Cells Transl Med. 2012; 1(7):557-65. PMC: 3659725. DOI: 10.5966/sctm.2012-0025. View

Said G . Diabetic neuropathy--a review. Nat Clin Pract Neurol. 2007; 3(6):331-40. DOI: 10.1038/ncpneuro0504. View

10.

Zhang J, Li S, Li L, Li M, Guo C, Yao J . Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinformatics. 2015; 13(1):17-24. PMC: 4411500. DOI: 10.1016/j.gpb.2015.02.001. View

11.

Goncalves N, Vaegter C, Andersen H, Ostergaard L, Calcutt N, Jensen T . Schwann cell interactions with axons and microvessels in diabetic neuropathy. Nat Rev Neurol. 2017; 13(3):135-147. PMC: 7391875. DOI: 10.1038/nrneurol.2016.201. View

12.

Shibata T, Naruse K, Kamiya H, Kozakae M, Kondo M, Yasuda Y . Transplantation of bone marrow-derived mesenchymal stem cells improves diabetic polyneuropathy in rats. Diabetes. 2008; 57(11):3099-107. PMC: 2570407. DOI: 10.2337/db08-0031. View

13.

Phinney D, Di Giuseppe M, Njah J, Sala E, Shiva S, St Croix C . Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015; 6:8472. PMC: 4598952. DOI: 10.1038/ncomms9472. View

14.

Zurita M, Vaquero J, Oya S, Bonilla C, Aguayo C . Neurotrophic Schwann-cell factors induce neural differentiation of bone marrow stromal cells. Neuroreport. 2007; 18(16):1713-7. DOI: 10.1097/WNR.0b013e3282f0d3b0. View

15.

Powell H, Rosoff J, Myers R . Microangiopathy in human diabetic neuropathy. Acta Neuropathol. 1985; 68(4):295-305. DOI: 10.1007/BF00690832. View

16.

Obrosova I, Ilnytska O, Lyzogubov V, Pavlov I, Mashtalir N, Nadler J . High-fat diet induced neuropathy of pre-diabetes and obesity: effects of "healthy" diet and aldose reductase inhibition. Diabetes. 2007; 56(10):2598-608. DOI: 10.2337/db06-1176. View

17.

Callaghan B, Cheng H, Stables C, Smith A, Feldman E . Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 2012; 11(6):521-34. PMC: 4254767. DOI: 10.1016/S1474-4422(12)70065-0. View

18.

Monaco F, Gaetani S, Alessandrini F, Tagliabracci A, Bracci M, Valentino M . Exosomal transfer of miR-126 promotes the anti-tumour response in malignant mesothelioma: Role of miR-126 in cancer-stroma communication. Cancer Lett. 2019; 463:27-36. DOI: 10.1016/j.canlet.2019.08.001. View

19.

Liu X, Fan B, Szalad A, Jia L, Wang L, Wang X . MicroRNA-146a Mimics Reduce the Peripheral Neuropathy in Type 2 Diabetic Mice. Diabetes. 2017; 66(12):3111-3121. PMC: 5697943. DOI: 10.2337/db16-1182. View

20.

Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood M . Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011; 29(4):341-5. DOI: 10.1038/nbt.1807. View