Diabetic nephropathy (DN) is a renal microvascular lesion caused by diabetes and is also one of the main causes of end-stage renal disease. Its clinical features are persistent albuminuria and/or a progressive decline in glomerular filtration rate. According to data from the International Diabetes Federation, the number of global diabetes patients is expected to reach 784 million by 2045 (Sun et al., 2022), and nearly 40 % of these diabetes patients will develop DN (Li et al., 2021). Currently, the treatment strategies for DN mainly focus on using oral hypoglycemic drugs to control blood glucose, and managing blood pressure and regulating blood lipids through drugs such as angiotensin-converting enzyme (ACE) inhibitors and statins. For end-stage DN patients, dialysis treatment (including hemodialysis and peritoneal dialysis) or kidney transplantation needs to be considered to maintain life and improve quality of life (QOL). However, effective treatment methods for DN are still relatively scarce. With the continuous increase in the number of DN patients, there is an urgent need to develop more effective treatment strategies (Hu et al., 2023).

Caplan (1991) first proposed the term "mesenchymal stem cells (MSCs)" in his paper, emphasizing that MSCs have the ability of self-renewal and the potential to differentiate into multiple cell types. MSCs were initially isolated and characterized from bone marrow. Subsequently, studies found that MSCs can also be extracted from a variety of tissues, including the umbilical cord, placenta, adipose tissue, skeletal muscle, liver, and lung (Mushahary et al., 2018). The anti-fibrotic, anti-inflammatory, anti-apoptotic properties of MSCs and their ability to differentiate into renal cells enable MSCs to play a crucial role in immune regulation and tissue repair, providing protective effects for the kidneys (He et al., 2024; Lu and Lerman, 2023; Wang et al., 2021a; Zhang et al., 2022b). Moreover, a retrospective analysis of the clinical application of MSCs during the period from 2006 to 2021 indicates that MSCs are of good safety. Their adverse reactions are mainly confined to mild and transient symptoms, such as fever, local reactions, insomnia, and constipation. Notably, no serious adverse events were reported (Wang et al., 2021b). Since MSCs have a wide range of sources, are almost free from ethical restrictions, have low immunogenicity, and high safety, and possess kidney-protective effects, they have become a highly promising treatment strategy for DN.

However, the persistent hyperglycemic and hyperlipidemic states in the bodies of DN patients lead to the accumulation of advanced glycation end-products (AGEs). Along with pathological changes such as renal microangiopathy, glomerulosclerosis, podocyte injury, and fibrosis, a complex microenvironment is formed. This microenvironment can inhibit the proliferation, migration, and differentiation abilities of MSCs (Yang et al., 2010; Zheng et al., 2024b). Therefore, successfully translating MSCs into clinically effective drugs for treating DN still faces numerous challenges, mainly including: (1) heterogeneity of cell sources and limitations in quality control; (2) low cell viability and survival rate; (3) low efficiency of directed differentiation; (4) insufficient targeted homing ability. This paper reviews existing research and finds that the effectiveness of MSCs in the treatment of DN can be further enhanced, and side effects reduced, through measures such as optimizing the culture conditions and cryopreservation protocols of MSCs, pretreating MSCs with drugs, using drugs in combination with MSCs, modifying MSCs with the help of biomaterial engineering and genetic engineering technologies, as well as optimizing the administration methods and dosages. Ultimately, these efforts can promote the clinical translation of MSCs, improve the QOL of DN patients, and slow down the progression of the disease.