MSC-CM and Its Potential in Kidney Disease Treatment

According to the World Health Organization’s 2019 estimation, chronic diseases are among the leading causes of death worldwide. Chronic kidney disease accounts for approximately 11 to 13% of global statistics. Kidney failure is a condition in which kidney function gradually diminishes over time, becoming irreversibly impaired. The leading causes of kidney failure can be attributed to various ailments such as diabetes, high blood pressure, kidney inflammation, urinary tract obstruction, medication use, or exposure to substances harmful to the kidneys. Based on the nature of the disease, kidney ailments are categorized into three types: acute kidney injury (AKI), chronic kidney disease (CKD), and end-stage renal disease (ESRD).

Current Common Kidney Failure Treatments

Kidney disease poses a formidable global challenge. Patients often must undergo weekly dialysis at a cost of about USD 80,000 annually. Meanwhile, there’s a lengthy waiting list for kidney transplants. Many patients cannot afford the treatment because of financial constraints, affecting their mental well-being and quality of life. Besides expensive current treatments, stem cell therapy has emerged as a promising, efficient, and accessible method for treating various kidney conditions, including acute and chronic kidney diseases (1).

The Mechanism of MSC-CM in Supporting Kidney Disease Treatment

Mesenchymal stem cell (MSC)-based therapies are the most advanced in clinical trial testing. First, MSCs can be easily expanded in a culture environment, generating many treatment doses. Accumulated evidence has demonstrated the significant therapeutic potential of MSCs in kidney diseases. While researchers haven’t discovered a unified mechanism regulating MSC-based therapy yet, existing data has revealed some working models driving their use (Figure 1) (2). MSCs’ mode of action typically relies on factors released into the environment during cell proliferation. Conditioned media from MSC culture contain various factors, such as growth factors, cytokines, extracellular vesicles, and other signaling molecules that could impact cell activities.

Figure 1: Mechanism of MSCs in Kidney Disease Treatment

Several studies show that MSC-CM has improved the survival of human kidney cells in both in vitro and in vivo settings (2-5). There’s increasing consensus that the kidney protective effects of MSCs primarily arise from their secretory function rather than direct transplantation. In kidney disease, conditioned environments have been studied for their potential to enhance kidney function and slow disease progression (2). Some research has investigated the effects of the conditioned environment on kidney diseases, particularly chronic kidney disease (CKD) and acute kidney injury (AKI) (6). Some reported effects of MSC-CM on kidney processes include:

• Regeneration of damaged kidney cells: CM promotes the regeneration of damaged kidney cells in animal models of AKI. Additionally, MSC-CM has inhibited the restructuring of the extracellular matrix induced by TGF-β1 and the transition from epithelial to mesenchymal cells in NRK-52E cells (7). This effect is believed to be due to the presence of growth factors and other stimulatory factors encouraging cell growth and division (8).
• Anti-inflammatory effects: Several studies reported CM reduces inflammation in the kidneys, a significant factor in CKD progression. After treatment with MSC-CM, kidney inflammation reduces, and the expression of fractal kine and IL-1RA, two cytokines involved in inflammatory reactions, increases. Although researchers haven’t confirmed the direct mechanism of this effect, they believe it is due to the presence of anti-inflammatory cytokines in the conditioned environment (9).
• Reduction of fibrosis: Fibrosis or scar tissue accumulation in the kidneys is a common characteristic of CKD. Some studies suggest that the conditioned environment can reduce kidney fibrosis, possibly by inhibiting the production of extracellular matrix proteins contributing to fibrosis (6, 9). In another study, MSC-CM reduced collagen type I and III deposition in kidney tubules (10).
• Protection against oxidative stress: The conditioned environment has been demonstrated to protect kidney cells against oxidative stress, a common feature of CKD and AKI. This effect is attributed to the presence of antioxidants in MSC-CM (1, 2).

Overall, researchers have found promising effects of MSC-CM on kidney disease, but they need to conduct more research to fully understand the mechanisms and develop effective therapies for patients. Subsequent clinical trials are necessary to assess the efficacy of MSC-CM.

References:

1. Rovira J, Diekmann F, Campistol JM, Ramírez-Bajo MJ. Therapeutic application of extracellular vesicles in acute and chronic renal injury. Nefrología (English Edition). 2017;37(2):126-37.
2. Wang J, Lin Y, Chen X, Liu Y, Zhou T. Mesenchymal stem cells: A new therapeutic tool for chronic kidney disease. Frontiers in Cell and Developmental Biology. 2022;10.
3. Huang Y, Yang L. Mesenchymal stem cells and extracellular vesicles in therapy against kidney diseases. Stem Cell Res Ther. 2021;12(1):219.
4. Wang S, Tong M, Hu S, Chen X. The Bioactive Substance Secreted by MSC Retards Mouse Aortic Vascular Smooth Muscle Cells Calcification. Biomed Res Int. 2018;2018:6053567.
5. Liu B, Ding FX, Liu Y, Xiong G, Lin T, He DW, et al. Human umbilical cord-derived mesenchymal stem cells conditioned medium attenuate interstitial fibrosis and stimulate the repair of tubular epithelial cells in an irreversible model of unilateral ureteral obstruction. Nephrology (Carlton). 2018;23(8):728-36.
6. Liu B, Ding FX, Liu Y, Xiong G, Lin T, He DW, et al. Human umbilical cord‐derived mesenchymal stem cells conditioned medium attenuate interstitial fibrosis and stimulate the repair of tubular epithelial cells in an irreversible model of unilateral ureteral obstruction. Nephrology. 2018;23(8):728-36.
7. Park JH, Hwang I, Hwang SH, Han H, Ha H. Human umbilical cord blood-derived mesenchymal stem cells prevent diabetic renal injury through paracrine action. Diabetes Research and Clinical Practice. 2012;98(3):465-73.
8. Sobh AL, Sobh MA. Mesenchymal stem cells versus their conditioned medium in the treatment of cisplatin-induced acute kidney injury: evaluation of efficacy and cellular side effects. Int J Clin Exp Med. 2016;9(12):23222-34.
9. Da Silva AF, Silva K, Reis LA, Teixeira VP, Schor N. Bone marrow-derived mesenchymal stem cells and their conditioned medium attenuate fibrosis in an irreversible model of unilateral ureteral obstruction. Cell transplantation. 2015;24(12):2657-66.
10. van Koppen A, Joles JA, van Balkom BW, Lim SK, de Kleijn D, Giles RH, et al. Human embryonic mesenchymal stem cell-derived conditioned medium rescues kidney function in rats with established chronic kidney disease. PloS one. 2012;7(6):e38746.