Stem Cells Created from Adult Kidney Cells May Help Combat Disease

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Researchers have genetically reprogrammed adult human kidney cells to become induced pluripotent stem (iPS) cells—a feat that may help in the study of kidney diseases and the development of novel therapies to treat them.

The findings could help millions of people with kidney disease, many of whom experience progression to end stage renal disease, which has only two treatment options: long-term dialysis or kidney transplantation. Effective alternatives are urgently needed for these patients, given the poor quality of life associated with dialysis and the increasing organ transplant waiting lists.

The study “Generation of induced pluripotent stem cells from human kidney mesangial cells” appears in the July issue of the Journal of the American Society of Nephrolology.

“This research is the stepping stone for the development of iPS cells from patients with kidney disease, particularly genetic kidney disease, which has an extraordinary potential for new drug discovery and personalized medicine,” said senior author Sharon Ricardo, PhD, of Monash University in Clayton, Victoria, Australia. “It will enable researchers to understand kidney disease in a way they have never been able to before.”

Reprogramming kidney cells

Researchers have recently succeeded in reprogramming certain somatic cells to produce iPS cells. For example, pluripotent cells can be derived from mouse and human fibroblasts by the induced expression of four transcription factors (OCT4, SOX2, KLF4, and c-Myc), and iPS cell lines can be generated from patients with certain genetic disorders.

In the current study, investigators questioned whether terminally differentiated kidney cells could be reprogrammed to pluripotency so that the resulting stem cells could differentiate into all three germ layers.

To answer this, Ricardo and her colleagues used normal human mesangial cells to derive iPS cell lines via genetic programming that consisted of transfection of 293FT cells with retroviral vectors containing the genes OCT3/4, SOX2, KLF4, and c-Myc. After several days, mesangial cells were reseeded on mouse embryonic fibroblast feeders. From 5 × 104 normal human mesangial cells, an average of 40 iPS colonies was observed. Numerous in vitro tests demonstrated that the kidney-derived iPS (kiPS) cells resembled human embryonic stem cell–like colonies in morphology and gene expression. For example, they were alkaline phosphatase positive; expressed OCT3/4, TRA-1-60, and TRA-1-81 proteins; and showed downregulation of mesangial cell markers. The kiPS cells expressed genes analogous to embryonic stem cells and showed silencing of the retroviral transgenes by the fourth passage of differentiation. In addition, the kiPS cells formed embryoid bodies and expressed markers of all three germ layers.

To test the cells’ pluripotency in vivo, three immunodeficient mice were injected with kiPS colonies. Encapsulated cystic teratomas formed in all mice and showed differentiated tissues from all three germ layers.

“Our study for the first time provides proof-of-concept for the direct nuclear reprogramming of adult human mesangial cells to generate kiPS cells,” the authors wrote.

Implications for the clinic

Patient-derived iPS cell lines generated by reprogramming somatic cells could have considerable importance in the clinic. “Induced pluripotent cells hold tremendous promise for stem cell and regenerative medicine,” said Benjamin Humphreys, MD, who is codirector of the Harvard Stem Cell Institute’s Kidney Group and was not involved with the research. “Since iPS cells appear to retain some molecular memory of their tissue of origin, this demonstration that kidney mesangial cells can be reprogrammed to pluripotency is an important step forward in developing this technology for disease modeling, toxicity testing, and ultimately cell therapy for patients suffering from kidney disease.”

Ricardo noted that through the study of an individual patient’s iPS cell line, researchers may be able to optimize that patient’s preventive and therapeutic care.

Others in the field are interested to see what advances come next. “This article shows that the renal field, like many others, is embracing the possibility that iPS cell generation may act as a source of stem cells for eventual use in the repair of kidney disease,” said Melissa Little, PhD, of the University of Queensland in St. Lucia, Queensland, Australia. “It should also be possible to make such cells from patients with genetic diseases such as polycystic kidney disease and potentially use them as tools to better understand such diseases,” she added.

Paola Romagnani, MD, of the University of Florence in Italy, noted that the research may also advance drug development. “Mesangial cell–derived iPS cells may be helpful for screening of novel pharmacological compounds for treatment of these renal disorders,” he said.

The study shows that human kidney biopsy specimens are a viable starting source for the generation of iPS cells,” Little said, but “what this does not address is how to take these cells and then regenerate useful renal cells for treatment.” To date, no one has developed a way of directing the differentiation of such cells into a kidney cell type.