Kidney disease is a prevalent global health problem. Stem cells are an attractive candidate as a form of regenerative medicine for kidney diseases. There have been increasing scientific evidences demonstrating the roles of stem cells in minimising damage while improving the function of kidney.
Kidney disease is a prevalent global health problem. According to the World Health Organization, as many as five to ten million people die annually from kidney diseases worldwide. Chronic kidney disease (CKD) is projected to be the fifth leading cause of death worldwide by 2040.
To date, the current available drugs or treatments can only delay the progression of the kidney disease yet cannot reverse the progression into the end-stage kidney disease. There has been no significant breakthrough in the medical treatment of kidney diseases. The current therapeutic choices to prolong the lifespan of patients with end-stage kidney disease are limited to kidney replacement therapies, such as dialysis and organ transplantation. Due to the high medical cost involved in dialysis therapy, it is is not an ideal solution because it fails to restore or substitute all kidney functions while also compromising the patients’ quality of life. Meanwhile, the severe shortage of organ donors and the risk of potential organ rejection limit the practice of kidney transplantations. Therefore, researchers should consider focusing on exploring innovative therapies that can improve the quality of life for people living with kidney illnesses.
Stem cells are cells that can self-renew and can transform into a variety of cell types. Moreover, stem cells can be easily expanded in vitro. Stem cells have been widely studied under in vitro, in vivo and clinical trial settings to treat many diseases including cardiac, neurological, vascular, immunological, and kidney diseases. This form of intervention can pave the way as the next regenerative medicine for human diseases.
Embryonic stem cells (ESCs) are pluripotent cells with unlimited differentiation potentials whereby one ESC can transform into a whole body cell type, including kidney cells. With the unique power of this type of cell, several research groups have demonstrated that mouse ESCs can integrate into kidney compartments suggesting the potential value of stem cells for kidney repair. To bring this idea further, researchers are working on generating the whole kidney structure from ESCs, termed as organoids.
However, despite its clinical potentials, the use of ESCs for regenerative medicine is compounded by the risks of tumour formation and the ethical concerns on the source of ESCs in the first place. ESCs are primarily made from cells found in a human blastula, one of the earliest stages of human life. There are views that destroying a blastula for its cells is akin to destroying an unborn child.
Induced pluripotent stem cells (iPSCs) share many regenerative properties as ESCs. This was a breakthrough finding that became a landmark in stem cell research. The development of iPSCsbased therapies could overcome the specific issues related to the use of ESCs, such as ethical concerns due to the cells’ source and the risks of cell rejection by the recipient patient. The potential of iPSCs in kidney regeneration have been explored, including establishing unique methods to stimulate human iPSCs to differentiate into kidney cells or three-dimensional structures of the kidney.
Mesenchymal stem cells (MSCs) were first found in bone marrow. Over the years, researchers have found that MSCs can be isolated from various organs or tissues. These stem cells have been demonstrated on their ability to differentiate into three lineages such as ectoderm, mesoderm and endoderm.
In the field of kidney disease, MSCs are among the most efficient type of cell population for activating regeneration in a damaged kidney. MSCs have demonstrated their ability to transform into renal components cell in vitro. When MSCs were injected into an animal with kidney disease, results showed that it can reduce further kidney damage. MSCs have three unique properties that enhance its potential in regenerative medicine. Firstly, MSCs have homing effect whereby after MSCs are injected into the body of an animal, the cells can migrate to the injury site. Secondly, MSCs have immunomodulation ability to decrease the inflammation at injury site which can reduce further damage. Thirdly, MSCs do not trigger immune response when transplanted to the recipient, which eliminates the risk of cell rejection by the recipient.
From commercial point of view, MSCs are a good cellular candidate to use under commercial setting because MSCs can be easily obtained from various organs or tissues and then grown into hundred- or thousand-times therapeutic dosage, and can be transplanted between individual humans i.e., allogeneically. Based on these many positive points, MSCs have become the main choice of stem cell in human translation research for regenerative medicine purposes.
Until March 2021, there are more than 40 clinical trials involving the use of stem cell-based therapy (mainly MSC) in the treatment of kidney diseases, either on-going or completed, registered in the U.S. National Library of Medicine.
The first few trials using MSCs from different tissue sources (bone marrow, adipose, umbilical cord, etc.), either autologously or allogeneically, suggested that these cells can be given safely to humans. In one study, few patients who had a high risk of post-operative AKI, underwent cardiac surgery, while concurrently received allogeneic MSCs. The patients had a shorter hospital stay and did not need readmission. In addition, this study concluded that the MSC infusion was safe and well-tolerated.
There are many human trials that use MSCs to treat CKD. A few pilot studies, assessing the safety and clinical feasibility of administration of MSCs for patients with CKD, reported that the cells were safe and did not result in any adverse effects. At the same time, improvement in kidney function was observed.
Currently, many clinical trials are still on-going and will provide more insights into and possibly further support these achievements with cellbased therapy for kidney diseases.
Other from stem cells-based therapy, researchers are exploring the usage of stem cell-derived extracellular vesicles. Extracellular vesicles (EVs) are small membrane vesicles secreted by various cells and found in most body fluids. The benefits of using EVs, as demonstrated by the researchers, are preventing tissue injury, reducing inflammation, inhibiting programmed cell death, and inducing cell cycle re-entry of resident cells, leading to cell proliferation, tissue self-repair and regeneration.
There are several advantages of using stem cell-derived EVs in clinical applications including avoiding most of the safety issues associated with stem cell treatment, i.e. cellular contamination with oncogenic cells and tumorigenicity. Furthermore, EVs offer a wide variety of possible modifications to the carrier molecules for the purpose of improving the distribution and desired effects.
Several studies show that intravenous MSC-derived EVs reduce cell damage and programmed cell death in the kidneys while enhancing the proliferation of the renal cells, resulting in improved kidney function. When EVs were administered in animal models with AKI and CKD, the animals experienced a reduction in kidney injury suggesting that the risks of cellular rejection is remarkably decreased.
Conclusion
Research on exploring stem cell-based therapies for kidney regeneration has shown promising results from in vitro and in vivo studies, and a well-accepted safety profile from early-phased human clinical trials. However, it will take some time before stem cell-based therapies become more significant proof of clinical efficacy for kidney diseases. Follow-up data from longer term is crucial to understand the potential long terms side effects of stem cell therapies on kidney diseases, especially to address the concerns on the use of live stem cells. More research can be done to evaluate EVs as a possible alternative to live stem cells especially as stem cells-derived EVs that can mimic its parental cells' effects in protecting the kidneys. A great future in the field of regenerative medicine is in store for stem cell therapy especially with regards to kidney regeneration.
References:
1. Luyckx, V.A., M. Tonelli, and J.W. Stanifer, The global burden of kidney disease and the sustainable development goals. Bull World Health Organ, 2018. 96(6): p. 414-422D.
2. Luyckx, V.A., et al., Sustainable Development Goals relevant to kidney health: an update on progress. Nat Rev Nephrol, 2021. 17(1): p. 15-32.
3. Liyanage, T., et al., Worldwide access to treatment for end-stage kidney disease: a systematic review. Lancet, 2015. 385(9981): p. 1975-82.
4. Vanholder, R., et al., Cost of renal replacement: how to help as many as possible while keeping expenses reasonable? Nephrol Dial Transplant, 2016. 31(8): p. 1251-61.
5. Saidi, R.F. and S.K. Hejazii Kenari, Challenges of organ shortage for transplantation: solutions and opportunities. Int J Organ Transplant Med, 2014. 5(3): p. 87-96.
6. Wong, C.Y., Current advances of stem cell-based therapy for kidney diseases. World J Stem Cells, 2021. 13(7): p. 914-933.
7. Rodríguez-Fuentes, D.E., et al., Mesenchymal Stem Cells Current Clinical Applications: A Systematic Review. Arch Med Res, 2021. 52(1): p. 93-101.
8. Geuens, T., C.A. van Blitterswijk, and V.L.S. LaPointe, Overcoming kidney organoid challenges for regenerative medicine. NPJ Regen Med, 2020. 5: p. 8.
9. Araoka, T., et al., Efficient and rapid induction of human iPSCs/ESCs into nephrogenic intermediate mesoderm using small molecule-based differentiation methods. PLoS One, 2014. 9(1): p. e84881.
10. Taguchi, A., et al., Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells. Cell Stem Cell, 2014. 14(1): p. 53-67.
11. Ullah, I., R.B. Subbarao, and G.J. Rho, Human mesenchymal stem cells - current trends and future prospective. Biosci Rep, 2015. 35(2).
12. Rota, C., M. Morigi, and B. Imberti, Stem Cell Therapies in Kidney Diseases: Progress and Challenges. Int J Mol Sci, 2019. 20(11).
13. Westenfelder, C. and F.E. Togel, Protective actions of administered mesenchymal stem cells in acute kidney injury: relevance to clinical trials. Kidney Int Suppl (2011), 2011. 1(3): p. 103-106.
14. Makhlough, A., et al., Bone marrow-mesenchymal stromal cell infusion in patients with chronic kidney disease: A safety study with 18 months of follow-up. Cytotherapy, 2018. 20(5): p. 660-669.
15. Villanueva, S., et al., Adipose tissue-derived mesenchymal stromal cells for treating chronic kidney disease: A pilot study assessing safety and clinical feasibility. Kidney Res Clin Pract, 2019. 38(2): p. 176-185.
16. Tang, T.T., et al., Extracellular Vesicles: Opportunities and Challenges for the Treatment of Renal Diseases. Front Physiol, 2019. 10: p. 226.
17. Biancone, L., et al., Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrol Dial Transplant, 2012. 27(8): p. 3037-42.
18. Vizoso, F.J., et al., Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int J Mol Sci, 2017. 18(9).
19. Park, K.S., et al., Enhancement of therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Stem Cell Res Ther, 2019. 10(1): p. 288.
20. Grange, C., et al., Stem Cell-Derived Extracellular Vesicles and Kidney Regeneration. Cells, 2019. 8(10).
21. Wu, X., et al., Micro-vesicles derived from human Wharton's Jelly mesenchymal stromal cells mitigate renal ischemia-reperfusion injury in rats after cardiac death renal transplantation. J Cell Biochem, 2018. 119(2): p. 1879-1888.
Wong Chee Yin is affiliated with University Tunku Abdul Rahman, Malaysia. With his vast experience of 20 years in stem cells research, he has published many related articles covering from lab-based to clinical translation studies.
