Successfully discovered stem cell markers to confirm the possibility of developing end-stage kidney disease cell therapy
Aug 14, 2024
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Professor Nam Ki-taek and Dr. Lee Yoo-ra's research team at Yonsei University School of Medicine announced on the 14th that Lrig1 kidney-embedded stem cells showed a regenerative effect when injected into the damaged kidney.
According to the Korean Kidney Society, the incidence of end-stage kidney disease in Korea was 360.2 per 1 million people in 2022, more than doubling from 2010. Treatment of end-stage kidney disease includes hemodialysis, peritoneal dialysis, and kidney transplantation. In the case of patients with end-stage kidney disease registered in Korea, 84% of hemodialysis patients, 6% of peritoneal dialysis patients, and 11% of kidney transplant patients are counted.
Dialysis treatment lowers the quality of life to the extent that the patient's daily life is difficult. Kidney transplants usually have a long waiting period of five to seven years, and even if they receive a transplant, side effects caused by immunosuppressants can occur.
In order to overcome the difficulties of dialysis and transplantation, research is being conducted on the development and application of cell therapy using stem cells.
Until now, research has mainly focused on cell therapy strategies that induce kidney cells using reverse differentiated stem cells, but there is a risk of tumor development when differentiation control is failed, so its suitability as a cell therapy for the treatment of end-stage kidney disease was questioned.
As a result, an alternative is to separate specific cells using intrinsic stem cell markers present in the kidney, induce differentiation into kidney cells, and transplant them into damaged kidneys. However, so far, the existence of stem cells in tissues that can regenerate damaged kidneys is unclear, so related research is at a standstill.
The research team presented the Lrig1 gene as a renal stem cell marker after studying the proximal tubule, the starting site of kidney injury. Lrig1 cells survive for a long time in various tissues such as the stomach, skin, and small intestine and are known to be involved in tissue regeneration.
The research team used a transgenic mouse model to track Lrig1 cells during the kidney development process throughout the life cycle, and confirmed that Lrig1 expression appeared in the kidney cortex from 13.5 days to adults in the mouse embryo stage.
Even when Lrig1-expressing cells isolated from the kidneys were cultured with organoids, single Lrig1+ cells were able to proliferate for a long time in vitro and differentiated into cells of the proximal tubule and collective tubule line. In addition, as a result of single-cell RNA sequencing analysis of cells expressing Lrig1, a gene reflecting the characteristics of stem cells was observed, and the possibility of Lrig1+ cells as intrinsic stem cells was proven at the molecular biological level.
The follow-up of Lrig1 differentiated cells in mouse kidneys showed that Lrig1 derived proximal tubular cells express abundant genes related to stem cell proliferation, contributing to the formation of renal proximal tubular and collective tubular structures. This confirmed that Lrig1 and its differentiated cells are stem cells that survive for a long time in kidney tissue and are involved in tissue homeostasis and regeneration.
Lrig1 and differentiated cells were actually involved in tissue regeneration even when Lrig1 cells were tracked by constructing an acute kidney injury mouse model to verify the results of the study. The research team evaluated the therapeutic ability by transplanting Lrig1-derived organoids into a mouse acute kidney injury model to confirm the applicability of Lrig1-based cell therapy.
In case of kidney injury, the kidney cannot properly remove waste from the blood, resulting in a more than 2-10 times increase in blood ureanitrogen (BUN) and creatinine levels compared to normal. As a result of checking the concentration of BUN and creatinine in the blood of kidney-damaged mice transplanted with Lrig1-derived organoids, the blood BUN and creatinine concentrations were restored to normal levels, and the expression of Kidney Injury Marker-1 (KIM1) protein, an indicator of kidney damage, was not observed.
Professor Nam Ki-taek said "The characteristics of Lrig1 cells in mouse kidneys are similar in human-derived Lrig1 cells, so it can be applied as an injury kidney treatment that can differentiate more stably than conventional stem cell-based cell therapy through separate culture of human-derived Lrig1 cells in the future."
Meanwhile, the results of this study were published in the international journal 『The Journal of the American Society of Nephrology』 (IF 13.6).
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