Exploring the Role of Mesenchymal Stem Cell–Derived Exosomes in Diabetic and Chemotherapy-Induced Peripheral Neuropathy

Painful diabetic neuropathy (PDN) is a challenging complication of diabetes with patients experiencing a painful and burning sensation in their extremities. Existing treatments provide limited relief without addressing the underlying mechanisms of the disease. PDN involves the gradual degeneration of nerve fibers in the skin. Keratinocytes, the most abundant epidermal cell type, are closely positioned to cutaneous nerve terminals, suggesting the possibility of bi-directional communication. Exosomes are small extracellular vesicles released from many cell types that mediate cell to cell communication. The role of keratinocyte-derived exosomes (KDEs) in influencing signaling between the skin and cutaneous nerve terminals and their contribution to the genesis of PDN has not been explored. In this study, we characterized KDEs in a well-established high-fat diet (HFD) mouse model of PDN using primary adult mouse keratinocyte cultures. We obtained highly enriched KDEs through size exclusion chromatography and then analyzed their molecular cargo using proteomic analysis and small RNA sequencing. We found significant differences in the protein and microRNA content of HFD KDEs compared to KDEs obtained from control mice on a regular diet (RD), including pathways involved in axon guidance and synaptic transmission. Additionally, using an in vivo conditional extracellular vesicle (EV) reporter mouse model, we demonstrated that epidermal-originating GFP-tagged KDEs are retrogradely trafficked into the DRG neuron cell body. Overall, our study presents a potential novel mode of communication between keratinocytes and DRG neurons in the skin, revealing a possible role for KDEs in contributing to the axonal degeneration that underlies neuropathic pain in PDN. Moreover, this study presents potential therapeutic targets in the skin for developing more effective, disease-modifying, and better-tolerated topical interventions for patients suffering from PDN, one of the most common and untreatable peripheral neuropathies.

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Human studies of the efficacy and safety of stem cells in the treatment of diabetic peripheral neuropathy: a systematic review and meta-analysis

Alizadeh,

Jahani,

Rukerd

et al. 2024

Stem Cell Res Ther

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Objective To assess the efficacy and safety of stem cell therapy in human studies for diabetic peripheral neuropathy (DPN). Methods A comprehensive literature review was performed across multiple databases, including Ovid MEDLINE ALL, Embase via Ovid SP, Scopus, Web of Science Core Collection, and Cochrane CENTRAL, up to January 31, 2024. Keywords and controlled vocabularies related to diabetic neuropathy and stem cell therapy were used. Inclusion criteria encompassed all controlled trials examining stem cell therapy for DPN, excluding animal or in vitro studies, review papers, conference abstracts, and editor letters. Data extraction and risk of bias assessment were independently performed by multiple reviewers using standardized tools. Results Out of 5431 initial entries, seven were included. Stem cell therapies included bone marrow-derived mononuclear cells and umbilical cord-derived mesenchymal stem cells, administered mainly via intramuscular transplantation. Meta-analysis indicated significant improvements in motor nerve conduction velocity (weighted mean differences (WMD): 2.2, 95% CI 1.6–2.8) and sensory nerve conduction velocity (WMD: 1.9, 95% CI 1.1–2.6). Vibration perception threshold and Toronto Clinical Scoring System scores decreased significantly (WMD: − 2.9, 95% CI − 4.0, − 1.8, and WMD: − 3.6, 95% CI − 5.0, − 2.2, respectively). Sensitivity analysis and subgroup analysis confirmed the robustness and specificity of these findings. The complications were pain and swelling at the injection sites, which disappeared in a few days. Conclusion Stem cell therapy shows significant promise in improving clinical outcomes for DPN, with evident benefits in nerve conduction and sensory parameters. Further research is needed to consolidate these findings and optimize therapeutic protocols. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-024-04033-3.

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Exploring the Role of Mesenchymal Stem Cell–Derived Exosomes in Diabetic and Chemotherapy-Induced Peripheral Neuropathy

Cited by 4 publications

References 127 publications

Keratinocyte-derived extracellular vesicles in painful diabetic neuropathy

Keratinocyte-derived extracellular vesicles in painful diabetic neuropathy

Keratinocyte-Derived Exosomes in Painful Diabetic Neuropathy

Human studies of the efficacy and safety of stem cells in the treatment of diabetic peripheral neuropathy: a systematic review and meta-analysis

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