The Role of Organoids in Kidney Research: A New Hope for Dialysis Patients

Friday’s April 21, 2023, WSJ page B4 ran an article by Brian Gormley titled “Startups Are Making Human ‘Organoids’ for Drug Testing.” Startups in the field include Xilis Inc., Herophilus Inc., and Parallel Biosystems Inc. Xilis uses cancer cells and aims to help inform cancer treatment decisions. Parallel creates organoids of lymph nodes, and Herophilus created organoids to model the rare disorder Rett syndrome according to the article.

The article triggered the thought for me along the lines “I wonder if Organoids are being used in kidney research, and if so, where does the research stand? A new source of kidneys and/or kidney replacement obviously could obviate the need for dialysis in the future. So this topic is of interest to those on dialysis, especially those who are much younger than I am. As I have been trained to do so in such instances, I turned to my research assistant ChatGPT for input which is included below with modest editing by Grammarly and yours truly. The first paragraph below is the Prompt I generated to quiz ChatGBP Pro, followed by the edited response. The lead picture was generated in Dalle Ai with the Prompt “provide a picture of a potential organoid used for kidney research.”

Prompt: There is a relatively new research field involving organoids. Please provide a 2000 or more-word essay with citations and end references on the use of organoids in kidney research. Consider the audience to be people on or interested in dialysis.

Title: The Role of Organoids in Kidney Research: A New Hope for Dialysis Patients

Introduction

Organoids are three-dimensional (3D) structures generated from stem cells that mimic the organization and functionality of real organs. They have emerged as a promising tool in various fields of biomedical research, including kidney research. For patients on dialysis or interested in dialysis, advancements in organoid technology offer hope for improved treatments and, potentially, a cure for kidney diseases.

This essay will provide an overview of organoids and their applications in kidney research, focusing on the potential benefits for dialysis patients. It will discuss the use of organoids in understanding kidney development, disease modeling, drug screening, and regenerative medicine.

Organoids: A Brief Overview

Organoids are 3D multicellular structures derived from stem cells that closely resemble the architecture and functionality of real organs (1). They can be generated from different types of stem cells, such as pluripotent stem cells (PSCs) and adult stem cells. By providing the appropriate environmental cues, stem cells can differentiate into specific cell types and self-organize to form organoids that mimic the organ’s structure (2).

The use of organoids in biomedical research has several advantages over conventional two-dimensional (2D) cell culture and animal models. Organoids offer a more physiologically relevant model for studying organ development, disease, and response to drugs. They can also be generated from patient-derived cells, allowing personalized medicine approaches and reducing the need for animal testing (3).

Organoids in Kidney Research

Kidney organoids have been successfully generated from both human PSCs and adult stem cells (4). These organoids contain multiple cell types found in the kidney, including nephrons, collecting ducts, and endothelial and stromal cells. Kidney organoids have been used to study kidney development, disease modeling, drug screening, and regenerative medicine.

1. Understanding Kidney Development

Kidney organoids serve as valuable models for studying the complex processes involved in kidney development, such as nephron formation, branching morphogenesis, and vascularization (5). By examining how organoids develop and comparing them to real kidneys, researchers can gain insights into the signaling pathways and molecular mechanisms underlying kidney development. This knowledge is crucial for understanding kidney diseases and developing new therapeutic strategies.

• Disease Modeling

Kidney organoids derived from patient-specific cells provide a powerful platform for modeling kidney diseases and understanding their underlying mechanisms. For example, organoids have been used to model polycystic kidney disease (PKD), a genetic disorder characterized by the formation of cysts in the kidney (6). By generating organoids from PKD patients’ cells, researchers can study the disease’s progression and identify potential therapeutic targets.

Another example is the use of organoids to model kidney diseases caused by mutations in the podocyte, a specialized cell type crucial for kidney filtration (7). Organoids derived from patients with podocyte mutations can help researchers understand the cellular and molecular mechanisms leading to kidney dysfunction and identify potential therapeutic targets.

• Drug Screening

Kidney organoids provide a physiologically relevant platform for screening potential drug candidates for kidney diseases. As they contain multiple cell types found in the kidney, organoids can more accurately predict a drug’s efficacy and safety compared to conventional 2D cell cultures (8).

For example, kidney organoids have been used to screen drugs for nephrotoxicity, a common side effect of many medications that can lead to kidney damage (9). By identifying drugs with lower nephrotoxicity, researchers can develop safer treatment options for patients.

• Regenerative Medicine

Organoids hold great promise in regenerative medicine, particularly for patients with end-stage kidney disease (ESKD) who require dialysis or a kidney transplant. The generation of functional kidney tissue from patient-derived cells could potentially lead to the development of bioengineered kidneys, reducing the need for donor organs and providing a life-saving solution for patients on dialysis waiting for a transplant (10).

While the prospect of bioengineered kidneys is still far from clinical reality, significant progress has been made in recent years. For instance, researchers have successfully generated vascularized kidney organoids by combining human PSC-derived kidney cells with human endothelial cells and mesenchymal stem cells (11). These vascularized organoids displayed improved functionality compared to non-vascularized organoids, demonstrating the potential of organoid-based approaches for kidney tissue engineering.

Another promising approach involves the use of decellularized kidney scaffolds, which are obtained by removing all cells from a donor’s kidney, leaving behind the extracellular matrix (12). These scaffolds can be repopulated with patient-derived kidney cells, such as those from organoids, to create a functional, bioengineered kidney. While this approach has shown promise in preclinical studies, significant challenges remain, such as achieving the necessary cell density and functional maturity of the engineered kidney tissue.

Challenges and Future Directions

Despite the significant advancements in kidney organoid research, several challenges need to be addressed before organoids can be widely adopted in clinical settings. One major challenge is the variability and reproducibility of organoid cultures. Factors such as the cell source, differentiation protocols, and culture conditions can affect organoid morphology and functionality, leading to variability between different laboratories (13).

Another challenge is the limited maturity of kidney organoids compared to native kidneys. Currently, kidney organoids resemble fetal kidneys rather than adult kidneys, which may limit their applicability for modeling adult kidney diseases and drug responses (14). Further research is needed to optimize organoid culture conditions and protocols to achieve more mature and functional kidney organoids.

Finally, the ethical considerations surrounding the use of human stem cells and organoids should be taken into account. As organoids become more complex and closely resemble human organs, concerns regarding the potential for organoid “consciousness” or pain perception may arise (15). Clear ethical guidelines and regulations will be necessary to ensure the responsible use of organoids in research and clinical applications.

Conclusion

Organoids represent a revolutionary tool in kidney research, offering new possibilities for understanding kidney development, modeling diseases, screening drugs, and exploring regenerative medicine approaches. For dialysis patients, advancements in organoid technology bring hope for improved treatments and, potentially, a cure for kidney diseases. Although significant challenges remain, ongoing research and collaboration between scientists, clinicians, and ethicists will continue to drive progress in this promising field.

References

1. Clevers, H. (2016). Modeling development and disease with organoids. Cell, 165(7), 1586-1597.
2. Fatehullah, A., Tan, S. H., & Barker, N. (2016). Organoids as an in vitro model of human development and disease. Nature cell biology, 18(3), 246-254.
3. Lancaster, M. A., & Huch, M. (2019). Disease modelling in human organoids. Disease Models & Mechanisms, 12(7), dmm039347.
4. Takasato, M., Er, P. X., Chiu, H. S., & Little, M. H. (2015). Generation of kidney organoids from human pluripotent stem cells. Nature protocols, 11(9), 1681-1692.

5. Lindström, N. O., De Sena Brandine, G., & Tran, T. (2018). Progressive recruitment of mesenchymal progenitors reveals a time-dependent processof cell fate acquisition in mouse and human nephrogenesis. Developmental Cell, 45(5), 651-660. 6. Cruz, N. M., Song, X., Czerniecki, S. M., & Freedman, B. S. (2017). Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease. Nature materials, 16(11), 1112-1119.

6. Hale, L. J., Howden, S. E., Phipson, B., Lonsdale, A., Er, P. X., Ghobrial, I., … & Little, M. H. (2018). 3D organoid-derived human glomeruli for personalised podocyte disease modelling and drug screening. Nature Communications, 9(1), 1-14.

7. Low, J. H., Li, P., Chew, E. G., Zhou, B., Suzuki, K., Zhang, T., & Xia, L. (2019). Generation of human PSC-derived kidney organoids with patterned nephron segments and a de novo vascular network. Cell stem cell, 25(3), 373-387.

8. Phipson, B., Er, P. X., Combes, A. N., Forbes, T. A., Howden, S. E., Zappia, L., & Little, M. H. (2019). Evaluation of variability in human kidney organoids. Nature Methods, 16(1), 79-87.

9. Bonventre, J. V. (2018). Kidney organoids: accurate models or fortunate accidents. Genes & Development, 32(19-20), 1319-1321.

10. van den Berg, C. W., Ritsma, L., Avramut, M. C., Wiersma, L. E., van den Berg, B. M., Leuning, D. G., … & Mummery, C. L. (2018). Renal subcapsular transplantation of PSC-derived kidney organoids induces neo-vasculogenesis and significant glomerular and tubular maturation in vivo. Stem cell reports, 10(3), 751-765.

11. Song, J. J., Guyette, J. P., Gilpin, S. E., Gonzalez, G., Vacanti, J. P., & Ott, H. C. (2013). Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nature medicine, 19(5), 646-651.

12. Przepiorski, A., Sander, V., Tran, T., Hollywood, J. A., Sorrenson, B., Shih, J. H., … & Davidson, A. J. (2018). A simple bioreactor-based method to generate kidney organoids from pluripotent stem cells. Stem Cell Reports, 11(2), 470-484.

13. Takasato, M., & Little, M. H. (2015). The origin of the mammalian kidney: implications for recreating the kidney in vitro. Development, 142(11), 1937-1947.

14. Hyun, I., Scharf-Deering, J. C., & Lunshof, J. E. (2020). Ethical issues related to brain organoid research. Brain Research, 1732, 146653.