Role of human umbilical cord mesenchymal stem cells in diabetic kidney disease

Abstract

One of the most prevalent long-term effects of diabetes is diabetic kidney disease (DKD), which is linked to problems with the metabolism of amino acids, fats, and carbohydrates. The fundamental pathogenic mechanisms of DKD cannot be adequately treated by current clinical medicines; they can only slow the illness’s progression to end-stage renal disease. We will concentrate on integrating human umbilical cord mesenchymal stem cell (hUC-MSC)-related mechanisms and potential applications into the therapy of DKD, as this work shows that hUC-MSCs can be used to treat metabolic liver obesity associated with diabetes. Future studies on the connection between hUC-MSCs and related illnesses ought to be promoted.

Key Words: Human umbilical cord mesenchymal stem cells; Diabetes; Diabetic kidney disease; Metabolic dysregulation; Metabolic dysfunction-associated steatotic liver disease; Diabetic complications

Core Tip: This letter to the editor focuses on investigating how human umbilical cord mesenchymal stem cells (hUC-MSCs) contribute to diabetic kidney damage. At the same time, explore the similarities and differences of hUC-MSCs in treating metabolic dysfunction-associated steatotic liver disease and diabetic kidney disease. There are benefits of using hUC-MSCs to treat metabolic disorders. Future studies on the relationship between hUC-MSCs and the management of metabolic disorders ought to be promoted.

TO THE EDITOR

We were intrigued by the paper “Human umbilical cord mesenchymal stem cells ameliorate liver metabolism in diabetic rats with metabolic-associated fatty liver disease” published by Zhou et al[1]. According to the study, diabetic rats with metabolic dysfunction-associated steatotic liver disease (MASLD) may benefit greatly from human umbilical cord mesenchymal stem cells (hUC-MSCs) therapy in terms of liver damage and anomalies in glucose and lipid metabolism[1]. With their numerous anti-inflammatory, anti-oxidative, islet-regeneration, and metabolic-regulating properties, hUC-MSCs have emerged as a highly effective therapeutic approach for the treatment of diabetes and its consequences. One of the most dangerous and prevalent side effects of diabetes is diabetic kidney disease (DKD), which is also a leading contributor to end-stage renal disease. The present clinical treatment is linked to numerous metabolic problems and is not optimal. The findings in this research offer a more comprehensive outlook and potential for stem cell treatment of DKD. Thus, the goal of this letter is to add to the mechanism of DKD treatment using hUC-MSCs.

This paper examined how hUC-MSCs affected the metabolism of the liver in diabetic rats suffering from MASLD. Three groups were created using diabetic rats as a model: The control group, the diabetes group, and the diabetes plus hUC-MSCs therapy group. According to the experimental findings, diabetic rats’ fasting blood glucose and serum triglyceride levels dropped, while liver damage and fat degeneration improved. HUC-MSCs are comparatively effective for MASLD, according to the study. Significant metabolic differences between the hUC-MSC treatment group and the diabetes group were revealed by the results of metabolomic analysis, indicating that hUC-MSC regulates liver metabolism. These major metabolic differences can also be used to properly diagnose diabetes associated with MASLD and to predict and impact the therapeutic effect of hUC-MSC in diabetes with MASLD. The metabolic regulatory treatment of MASLD is given a new paradigm by this study, which also offers suggestions for potential clinical treatments.

This article’s hUC-MSCs can enhance MASLD’s lipid and glucose metabolism, which also applies to DKD. DKD can develop as a result of hyperglycemia and lipotoxicity, which can cause oxidative stress, an inflammatory response, and apoptosis. These conditions can also directly harm glomeruli, podocytes, and renal tubules. Given that DKD and MASLD share a route of insulin resistance and lipotoxic damage, clinical evidence reported by Targher et al[2] indicates that individuals with MASLD have a markedly elevated chance of acquiring DKD. In addition, fundamental research has demonstrated that hUC-MSCs enhance insulin sensitivity and intrahepatic lipid metabolism while lowering aberrant lipids through the activation of the liver’s hepatocyte nuclear factor 4 alpha/carboxylesterase 2 pathway. Because of its systemic nature, this action can directly lessen kidney damage[3]. Therefore, improving glucose and lipid metabolism in patients with MASLD can also effectively reduce the risk of DKD. In addition, hUC-MSCs can also reduce lipid deposition in the kidneys of DKD rats[4]. They can also reduce the release of pro-inflammatory cytokines by improving blood glucose levels in DKD mouse models, thereby reducing renal fibrosis and other pathological changes[5].

Furthermore, the sirtuin 1 (SIRT1) pathway is shared by the liver and kidney in preserving cellular homeostasis and fending off inflammation and oxidative stress (Figure 1). The kidney and liver share the SIRT1 pathway, which helps to maintain cell homeostasis in the face of inflammation and oxidative damage. The SIRT1 pathway, which improves mitochondrial function, increases autophagy, suppresses inflammation, and controls cell death in both hepatocytes and kidney cells, can be activated in the liver and kidney by hUC-MSCs therapy[6,7]. Naturally, the SIRT1 pathway protects the kidneys and liver, but tissue specificity affects how active it is. In addition to the previously described hUC-MSCs therapy, which enhances glucose and lipid metabolism, this is still another popular treatment approach that targets metabolic impairment in several organs. However, the kidney exhibits distinct organ specificity in contrast to the liver studies discussed in this article. For instance, podocytes are an essential part of the glomerular filtration barrier and are in charge of stopping protein leakage. One of the main processes causing reduced renal function in DKD is capsular cell damage and death. HUC-MSCs can preserve podocytes through exosomes[8], which is crucial for slowing the course of DKD.

Figure 1 Mechanism of human umbilical cord mesenchymal stem cells action via the sirtuin 1 pathway common to kidney and liver. SIRT1: Sirtuin 1; hUC-MSCs: Human umbilical cord mesenchymal stem cells.

Furthermore, certain decreases in blood creatinine, urea nitrogen, and urine protein levels, together with an increase in glomerular filtration rate or creatinine clearance, demonstrate that hUC-MSC therapy can preserve and enhance kidney function[9,10]. Additionally, it can lessen the severity of renal tubular injury, glomerulosclerosis, and renal fibrosis[11,12], and it may offer a means to repair glomerular sclerosis and lower inflammation in DKD animals[13]. According to the aforementioned article, hUC-MSCs have a variety of therapeutic uses and could one day be used to treat further diabetic problems as well as other metabolic disorders.

Transplanting hUC-MSCs into mice is known as allogeneic transplantation, and it can cause immunological depletion, short-term adverse effects, and other problems. In the meantime, syngeneic transplantation of mouse umbilical cord mesenchymal stem cells might exhibit more profound symptoms of recovery[14]; nevertheless, there is currently very little research on rat umbilical cord mesenchymal stem cells targeting MASLD or other disease models, and there is a lack of actual experimental data to support the theoretical assumptions described above. More study is currently being done on hUC-MSCs because of their robust proliferative ability, low immunological response, and low danger of contamination.

According to the article, using hUC-MSCs to treat MASLD and DKD requires addressing distinct pathological centers and damage mechanisms in the liver and kidneys, as well as variations in treatment outcomes and evaluation standards at the conclusion of the course of treatment. As a result, as the paper points out, there are several obstacles to study on hUC-MSCs in the treatment of DKD and MASLD, including the instability of mixed cell injections, a dearth of long-term clinical data, and unidentified possible adverse effects. However, as the article notes, hUC-MSCs have the ability to treat both MASLD and diabetes, and ongoing research initiatives continue to hold out hope for the treatment of DKD using hUC-MSCs. To continue verifying efficacy and evaluating the treatment’s long-term benefits and possible adverse effects, we must carry out comprehensive mechanistic research and clinical trials in a variety of animal models in the future.