According to the International Diabetes Federation, diabetes mellitus currently affects approximately 425 million people worldwide, with projections suggesting that the number could exceed 700 million by 2045 (Sun et al., 2022). Diabetic neuropathy is an early-developing complication of diabetes characterized by axonal degeneration, demyelination, and impaired nerve regeneration. Rest pain, hyperalgesia, and diminished sensation due to diabetic neuropathy affect approximately half of all diabetics, not only dramatically reducing their quality of life but also placing a significant burden on the healthcare system (Pacifico et al., 2023). Although rigorous glucose control can slow the progression of diabetic neuropathy, it is not effective in restoring the function of damaged nerves (Ismail, 2023). Therefore, innovative strategies to improve nerve function in diabetic neuropathy are urgently needed.

Cell-based therapies are considered a promising approach to disease modification due to their ability to harness the body’s healing mechanisms. In particular, mesenchymal stem cells (MSCs), a group of non-hematopoietic stem cells derived from the mesoderm, have attracted considerable attention because of their low immunogenicity, remarkable tissue regeneration potential, and powerful immunomodulatory capacity (Ebrahimi et al., 2023). Furthermore, MSCs are readily available, as they can be isolated from various tissues, including but not limited to bone marrow, adipose tissue, and teeth; they are able to multiply rapidly in vitro, undergoing several to a dozen passages (Li and Wang, 2022). Importantly, clinical trials from different countries have demonstrated the safety of MSCs, as evidenced by the fact that no allergic or severe adverse reactions were observed up to years after years of transplantation (Arango-Rodríguez et al., 2023; Razak et al., 2023; Xie et al., 2023). Therefore, treatment of MSCs could offer significant potential in treating tissue damage and functional disorders.

The complexity of diabetic neuropathy derives from its multifaceted interplay of nerve damage, impaired blood supply, and chronic inflammation (Eid et al., 2023). The multifunctional nature of MSCs enables them to exert therapeutic effects through multiple mechanisms. Transplanted MSCs can not only directly participate in tissue regeneration by differentiating into various cell types, such as Schwann cells and vascular endothelial cells, but they can also influence neighboring cells through their paracrine activity (Abuarqoub et al., 2020; Wang et al., 2022). It has been well-established that the secretome of MSCs comprises a diverse array of bioactive molecules that are beneficial for nerve repair. These include neurotrophic factors such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT3), and glial cell line-derived neurotrophic factor (GDNF); angiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF); as well as anti-inflammatory cytokines, particularly interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) (Trzyna and Banaś-Ząbczyk, 2021; Drobiova et al., 2023). Consistent with in vitro studies, preclinical animal studies have also demonstrated that MSC transplantation significantly relieves the symptoms and slows the progression of diabetic neuropathy, as evidenced by improvements in both motor and sensory nerve function, increased limb blood flow to the limbs, and a reduced inflammatory response (Shibata et al., 2008; Kim et al., 2011; Waterman et al., 2012; Guimarães et al., 2013; Himeno et al., 2013; Hata et al., 2015; Xia et al., 2015; Han et al., 2016; Omi et al., 2016; Brini et al., 2017; Datta et al., 2017; Monfrini et al., 2017; Omi et al., 2017; Abdelrahman et al., 2018; Evangelista et al., 2018; Xie et al., 2019; Hata et al., 2020; He et al., 2020; Kanada et al., 2020; Hata et al., 2021; Pan et al., 2022; Yigitturk et al., 2022; Yang et al., 2023).

Since the clinical application of MSCs in the treatment of diabetic neuropathy is at an early stage, a thorough and rigorous systematic review and meta-analysis of preclinical evidence can greatly help scientists and clinicians in designing and conducting clinical trials. To this end, we reviewed animal studies focused on the use of MSCs for the treatment of diabetic peripheral neuropathy (DPN), obtained from major databases, including PubMed, Web of Science, Embase, and Cochrane library. The main characteristics of the included articles were summarized, and the effectiveness of MSC transplantation on nerve function, blood supply, and inflammation was assessed. We hope that this systematic review and meta-analysis will serve as a basis for incorporating MSCs into the clinical treatment of diabetic neuropathy.

To the best of our knowledge, this is the first systematic review and meta-analysis that provides a comprehensive synthesis of the preclinical efficacy of MSCs in the treatment of DPN. Pooled estimates from meta-analyses support the hypothesis that MSCs offer significant therapeutic benefits on neural function (i.e., motor and sensory nerve conduction velocities and intra-epidermal nerve fiber density) and vascularization (i.e., sciatic nerve blood flow and capillary-to-muscle fiber ratio). Additionally, the review revealed that the benefits of MSCs may be associated with an increase in neurotrophic factors and angiogenesis, along with an inhibition of inflammatory reactions. These findings suggest that MSC-based therapy could be a promising strategy for the treatment of DPN.

Among the MSCs sourced from various tissues, dental pulp stem cells (DPSCs) and bone marrow mesenchymal stem cells (BMSCs) are the most favored by researchers, being utilized in about two-thirds of the included studies (DPSCs: n = 8; BMSCs: n = 8). DPSCs can be isolated from fallen deciduous teeth or from teeth extracted for orthodontic reasons (e.g., impacted third molars). The easy accessibility of DPSCs makes them a compelling source for cell therapy (Datta et al., 2017). BMSCs were the first MSCs to be discovered, and their safety and efficacy have been confirmed through extensive clinical applications (Chu et al., 2020). Both DPSCs and BMSCs have shown significant potential for restoring nerve dysfunction; however, direct evidence comparing their therapeutic effects on DPN is lacking. Furthermore, the low immunogenicity of MSCs allows the possibility of cross-species transplantation: rodents in nine studies received MSCs derived from human tissue, but no immune rejection was reported (Waterman et al., 2012; Xia et al., 2015; Brini et al., 2017; Datta et al., 2017; Xie et al., 2019; Hata et al., 2020; Hata et al., 2021; Pan et al., 2022; Yang et al., 2023).

Hyperglycemia, the main feature of diabetes, leads to metabolic disorders, redox status imbalance, and cellular dysfunction, all of which contribute to the fundamental pathological basis of DPN (Kaur et al., 2023). 10 of the 23 included studies provide information on the effects of MSCs on hyperglycemia control. After MSC administration, significant decreases in blood glucose were observed in five studies, but rodents in these treatment arms still met the diagnostic criteria for diabetes. MSCs may exert their beneficial effects both by differentiating into pancreatic islet cells and by secreting an array of growth factors that can rejuvenate pancreatic islet cells, such as insulin-like growth factor 1 (IGF-1), pancreatic and duodenal homeobox 1 (PDX-1), and glucagon-like peptide-1 (GLP-1) (Sionov and Ahdut-HaCohen, 2023). Despite these outcomes, MSCs were unable to normalize the blood glucose levels in diabetic rodents, suggesting that their ability to regulate blood glucose may be not as robust as their neurotrophic and angiogenesis functions. This finding suggests that the therapeutic effect of MSCs could be further enhanced by the simultaneous use of hypoglycemic agents.

DPN usually starts with abnormal sensations in the extremities, often accompanied by gradually worsening pain (Pacifico et al., 2023). In later stages, motor nerve involvement may occur, manifesting as decreased muscle tone and strength, ultimately leading to muscle atrophy and paralysis. The conduction velocity of motor and sensory nerves is a sensitive indicator of the condition of limb nerves, and its abnormality often occurs before the clinical manifestations of DPN. A Meta-analysis of 16 treatment arms from 12 included studies showed that MSC administration significantly alleviated delayed motor nerve conduction. The findings were supported by the pooled estimates of sensory nerve conduction from 9 treatment arms in 8 studies. Furthermore, MSC transplantation significantly increased the density of epidermal nerve fibers, suggesting an improvement in the degeneration of terminal nerves. Several studies attributed the benefits of MSCs to their ability to upregulate the levels of neurotrophic factors, such as bFGF and NGF (Han et al., 2016; Hata et al., 2020; Kanada et al., 2020). It is believed that the increase in neurotrophic factors originates not only from the MSCs but also from the cells rejuvenated by them (Yue et al., 2016).

In addition to nerve damage, microangiopathy is also a characteristic pathological feature of DPN. This pathological process is associated with endothelial dysfunction, thickening of the capillary endothelial basement membrane, microcirculatory disorders, and impaired angiogenesis (Fang et al., 2018). Nerve cells rely highly on oxygen and energy; consequently, ischemia resulting from diabetic microangiopathy causes them significant harm. As the longest and thickest peripheral nerve, the sciatic nerve is often the first and most severely affected nerve by diabetic microangiopathy (Kender et al., 2023). Seven studies reported an increase in sciatic nerve blood flow after the administration of MSCs, with a meta-analysis of eight treatment arms showing no significant heterogeneity. The results indicated that the increased blood supply to the sciatic nerve plays a crucial role in the beneficial effects of MSCs on nerve conduction velocity and nerve dysfunction. Furthermore, pooled estimates from seven studies showed an increased ratio of blood vessels to muscle fibers in MSC-treated animals, suggesting an improvement in microcirculation disorder due to MSC treatment.

The inflammatory response helps eliminate pathogens and foreign bodies, and can also activate the body’s natural repair mechanisms. However, when this inflammation becomes chronic and uncontrolled due to diabetes, it can cause considerable damage to the nervous and circulatory systems (Cheng et al., 2024). The immunoregulatory ability of MSCs is also a key factor in their role in neuroprotection and tissue regeneration. It has been reported that the secretome of MSCs contains an abundance of anti-inflammatory factors, such as PGE2, IL-10, IL-35, and TGF-β (Trzyna and Banaś-Ząbczyk, 2021). Furthermore, recent preclinical evidence has revealed that the administration of MSCs can convert a significant proportion of macrophages from a pro-inflammatory phenotype (M1) to an anti-inflammatory phenotype (M2) (Liu et al., 2022). Indeed, several included studies reported a decrease in pro-inflammatory cytokines, including TNF-α and IL-1, and an increase in the anti-inflammatory factor IL-10 in the peripheral nerves, spinal cord and plasma (Omi et al., 2016; Brini et al., 2017; Datta et al., 2017). However, researchers used different methods when assessing inflammation in different tissues, including PCR, ELISA, Western blotting, and immunohistochemistry. This methodological heterogeneity made a meta-analysis not feasible.

We must acknowledge several limitations in this systematic review and meta-analysis. First, all included studies used rodents as animal models, which may exaggerate the treatment effects of MSCs on DPN. Second, although most meta-analysis results showed low heterogeneity, the sample size in each case was limited; Studies with larger samples are urgently needed to provide more robust evidence. Third, the data extracted using the GetData software may have slight differences from the original data.

Overall, MSC therapy showed significant benefits in both neuroprotection and angiogenesis, as evidenced by a number of improvements in MSCs-treated animals compared with the control animals, including enhanced conduction velocity of motor and sensory nerves, denser epidermal nerve fibers, increased sciatic nerve blood flow, and a higher ratio of blood vessels to muscle fibers. The treatment effects of MSCs could also be related to their anti-inflammatory function, but a meta-analysis was not feasible due to the significant methodological differences across studies. These findings suggest that MSC transplantation holds promise as a strategy for DPN. However, rigorous and well-designed preclinical and clinical trials with larger sample sizes remain essential.

This systematic review and meta-analysis evaluated the preclinical efficacy of MSCs in the treatment of diabetic neuropathy. A comprehensive analysis of 23 animal studies suggests that MSC therapy holds significant potential to improve various aspects of diabetic neuropathy. Pooled analyses indicated that MSC administration resulted in improvements in motor and sensory nerve conduction velocities, increased intra-epidermal nerve fiber density, improved sciatic nerve blood flow, and favorable modulation of the capillary-to-muscle fiber ratio. Additionally, MSC treatment was associated with the upregulation of neurotrophic factors, an increase in angiogenic factors, and a reduction in inflammatory cytokines. While MSCs emerge as a promising avenue for treating diabetic neuropathy based on preclinical models, further research, particularly well-designed clinical trials, is essential to fully understand their therapeutic potential and facilitate their integration into clinical practice.