Scientists at Nanyang Technological University, Singapore (NTU Singapore), have made a crucial breakthrough by successfully growing “mini kidneys” in the lab and grafting them into live mice. This novel method has revealed a new understanding of the metabolic defects associated with polycystic kidney disease (PKD) and offers potential therapeutic methods for this genetic condition. PKD affects approximately one in every thousand individuals across all ethnicities and often leads to end-stage kidney disease between the ages of 50 and 60.
Simultaneously, researchers at UC San Francisco (UCSF) and Cedars-Sinai are pioneering techniques to program stem cells to form rudimentary organs, further fueling the promise of lab-grown organs. These parallel breakthroughs highlight a rapidly evolving field that promises to possibly revolutionize healthcare.
Understanding Polycystic Kidney Disease (PKD)
PKD is a prevalent genetic disorder described by the formation of cysts in the kidneys, which can lead to kidney failure. The only current treatment options available for PKD include dialysis, kidney transplantation, or the use of an FDA-approved drug, Tolvaptan. However, dialysis significantly impacts a patient’s quality of life, diminishing it. A kidney transplantation is challenging due to the scarcity of available kidneys. Another option is receiving Tolvaptan, although quite an effective drug, is expensive and has severe side effects on the liver. Therefore, there is a pressing need for more effective and personalized treatments for PKD patients.To address the need for more effective treatment for PKD patients, the NTU research team engrafted their newly developed mini kidneys into mice to better understand the disease.
The Development of Mini Kidneys
The NTU research team, led by the Lee Kong Chian School of Medicine (LKCMedicine), has developed these “mini kidneys” using stem cells derived from the skin cells of patients with PKD. These kidney organoids are kidney-like structures that imitate the structure and function of human kidneys to some extent. Unlike previous studies that grew mini kidneys in a dish, the NTU team took a more advanced approach by engrafting their mini kidneys into live mice. This method allowed them to replicate the complex pathological features of kidney disease more accurately, including blood flow, fluid movement, and cellular communication with other organs.
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Advantages of Engrafting Mini Kidneys into Mice
Engrafting mini kidneys into mice offers a highly advanced way to study PKD, as these mini kidneys closely mimic the complex functions of real human kidneys, which helps researchers study PKD more effectively. According to Assistant Professor Xia Yun, this method enabled the team to emulate disease characteristics and abnormalities similar to those observed in human kidney patients. The mini kidneys spontaneously formed cysts on their own without any need for stress stimulation or chemicals. This is a big step up from previous organoids grown in a dish, which required stress stimulation to form cysts.
Metabolic Defects and Autophagy
Scientists have long recognized that abnormalities in the primary cilium, a structure on kidney cells, contribute to cyst formation in PKD (parenchymal renal disease). However, understanding the relationship between the primary cilium and cell metabolism (autophagy) in live models has been challenging until now. By studying PKD in live mice, the NTU team found evidence that boosting autophagy could reduce the severity of cysts in the mini kidneys. This discovery suggests that bolstering autophagy could be a promising therapeutic treatment for PKD.
Testing Potential Therapies
Following the discovery that boosting autophagy reduces cyst formation, the NTU researchers tested 22 drugs known for their effects on cell metabolism. Among these, minoxidil – a clinical drug commonly used to treat hypertension and hair loss – was found to be effective in reducing cyst formation in the mouse model. The proven clinical safety of minoxidil makes it a promising potential candidate for repurposing as a treatment for PKD, although further research is needed to confirm its efficacy in treatment.
Future Directions
The NTU team plans to continue testing the efficacy of minoxidil and adapt their mini kidney models to investigate other kidney diseases, such as diabetic kidney disease, which lacks a strong genetic foundation. This approach could lead to more personalized and effective treatments for various kidney diseases. As noted by Associate Professor Ng Kar Hui, an effective treatment for PKD could significantly impact the rising numbers of people with kidney failure, particularly in Singapore.
Personalised Medicine and Drug Testing
One of the significant benefits of using mini kidneys is the ability to tailor treatment plans to individual patients. Since genetic errors causing kidney diseases vary from person to person, personalized organoids can help researchers determine which drugs are most effective for each patient. This approach removes the need for drug screening on actual patients, reducing potential risks and improving treatment outcomes.
Engineering Organizer Cells to Build Organs from Scratch
While NTU’s work focuses on refining existing models, researchers at UCSF and Cedars-Sinai are tackling the challenge of “building from the bottom” organ creation. Their approach centres around engineered “organiser” cells – specialised cells that can direct stem cell differentiation into specific tissues. Traditional organiser cells have limitations in their ability to apply complex growth programs.
Wendell Lim, PhD, a professor at UCSF, and Ophir Klein, MD, PhD, executive vice dean at Cedars-Sinai, developed synthetic “organizer” cells capable of sending customized growth signals to stem cells. By manipulating the placement and signalling patterns of these organiser cells, they can control gene expression in stem cells, coaxing them to build rudimentary cell structures.
The outcomes of experimentation: Lab Grown Organs
In an incredible experiment, this technique formed structures resembling heart ventricles—complete with rhythmic contractions and rudimentary blood vessels. Researchers previously created beating cells in Petri dishes. However, the well-defined chamber and vessel-like appendages on the structures now represent a significant advancement toward creating functional lab-grown organs. This research demonstrates a notable leap forward in regenerative medicine.
The Future of Lab Grown Organs: How Close Are We?
The progress in both NTU’s mini kidney models and UCSF/Cedars-Sinai’s organizer cell technology highlights the accelerating pace of regenerative medicine. However, achieving fully functional, transplantable organs remains a complex challenge. Ultimately, the combined efforts of researchers like those at NTU and UCSF/Cedars-Sinai offer a beacon of hope for patients suffering from organ failure and genetic diseases. The journey towards fully functional lab-grown organs is complex, but the progress made thus far demonstrates that this transformative technology is steadily moving closer to reality.
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