Introduction:
The global burden of Acute kidney injury (AKI)-related mortality is greater than that of heart failure, breast cancer, or diabetes, and mortality has remained high over the last 50 years (1). AKI is a group of related diseases that is the most common reason for nephrology consultations. Despite the advances in our understanding of AKI-CKD pathophysiology, as the disease progresses, the only available endpoint therapy options are dialysis and kidney transplantation (2,3). Since the majority of AKI patients suffer from CKD, we propose a novel therapy targeting the transition from AKI to CKD. Mesenchymal stem cells (MSCs) have proven to be a feasible choice for kidney disease therapy due to their antiapoptotic, immunomodulatory, antioxidative, and pro-angiogenic activities (4–6). However, the clinical translation of the same is at a miniscule level (7,8). In this study, we have preconditioned MSCs with formulation A for them to exert a strong anti-fibrotic effect in conjunction with anti-inflammatory and immunomodulatory effects. Since the preconditioning is exerting these effects in in vitro models of primary cultures of kidney-derived cells, we plan to test this hypothesis in the AKI-CKD animal model.
Methods:
Primary cell culture of interstitial fibroblasts was established by sieving method (9). The MSCs were isolated from the explant culture of Wharton jelly from the discarded clinical waste after patients' due consent. Both cell types were cultured, and characterized in GMP-compliant facilities. MSCs were preconditioned with formulation A at a standardized concentration and time point, the concentrated conditioned medium was collected by using centrifugal filters (cut-off 3kDa MW). The concentrated medium from these cells was tested in a cisplatin-mediated injury model of interstitial fibroblasts. The efficacy of MSCs was checked in terms of their viability, phenotyping, and functional capabilities like immunomodulation. Endpoints of in vitro work were studied in the context of inflammatory markers by ELISA and fibrotic markers by immunofluorescence.
Results:
We have shown that the specific preconditioning of MSCs improves their immunomodulation capability markedly while maintaining a good viability score. Moreover, the secretome from these MSCs imparts an anti-inflammatory and anti-fibrotic milieu in the in vitro injury and diseased models of human kidney-derived primary interstitial fibroblast cells.
Conclusions:
We have demonstrated that conditioned MSC secretome treatment to a diseased milieu of primary human kidney cells leads to a decrease in the expression of apoptotic, fibrotic, and inflammatory markers. Here, we propose that this secretome-based intervention could be an ideal therapeutic contender once tested in a preclinical model because:
- It is a cell-free therapy, and It has the potential to generate an off-shelf therapeutic product.
References:
1. Lewington AJ, Cerdá J, Mehta RL. Raising Awareness of Acute Kidney Injury. Kidney Int. 2013;84(3):457–67.
2. Câmara NOS, Iseki K, Kramer H, Liu ZH, Sharma K. Kidney disease and obesity: Epidemiology, mechanisms and treatment. Nat Rev Nephrol. 2017;13(3):181–90.
3. Susantitaphong P, Cruz DN, Cerda J, Abulfaraj M, Alqahtani F, Koulouridis I, et al. World incidence of AKI: A meta-analysis. Clin J Am Soc Nephrol. 2013;8(9):1482–93.
4. Zhuang WZ, Lin YH, Su LJ, Wu MS, Jeng HY, Chang HC, et al. Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications. J Biomed Sci. 2021;28(1).
5. Tsubokawa T, Yagi K, Nakanishi C, Zuka M, Nohara A, Ino H, et al. Impact of anti-apoptotic and anti-oxidative effects of bone marrow mesenchymal stem cells with transient overexpression of heme oxygenase-1 on myocardial ischemia. Am J Physiol - Hear Circ Physiol. 2010;298(5):1320–9.
6. Hoogduijn MJ, Popp F, Verbeek R, Masoodi M, Nicolaou A, Baan C, et al. The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy. Int Immunopharmacol. 2010;10(12):1496–500.
7. Zhou T, Yuan Z, Weng J, Pei D, Du X, He C, et al. Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol. 2021;14(1):1–24.
8. Chen F, Chen NN, Xia C, Wang H, Shao L, Zhou C, et al. Mesenchymal Stem Cell Therapy in Kidney Diseases: Potential and Challenges. Cell Transplant. 2023;32(374).
9. Liu X, Liu Z, Wang C, Miao J, Zhou S, Ren Q, et al. Kidney tubular epithelial cells control interstitial fibroblast fate by releasing TNFAIP8-encapsulated exosomes. Cell Death Dis. 2023;14(10):1–15
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.