Accelerating Stem Cells Aging To Study Age-Related Diseases Like Parkinson’s

Using stem cells to model neurodegenerative diseases shows terrific promise, but because the stem cells tend to produce young cells, they often fail to accurately model disorders that show late-onset. To solve this problem, a research group has published a paper in the December 5th edition of the journal Cell Stem Cell that describes an ingenious new method that converts induced pluripotent stem cells (iPSCs) into nerve cells that recapitulate features associated with aging as well as Parkinson’s disease. This simple approach, which involves exposing iPSC-derived cells to a protein associated with premature aging called “progerin,” could provide a way for scientists to use stem cells to model a range of late-onset disorders. This technique could potentially open new avenues for preventing and treating these devastating diseases.

“With current techniques, we would typically have to grow pluripotent stem cell-derived cells for 60 or more years in order to model a late-onset disease,” says senior study author Lorenz Studer of the Sloan-Kettering Institute for Cancer Research. “Now, with progerin-induced aging, we can accelerate this process down to a period of a few days or weeks. This should greatly simplify the study of many late-onset diseases that are of such great burden to our aging society.”

Induced pluripotent stem cells allow scientists to model a specific patient’s disease in a culture dish. By extracting a small sample of skin cells and genetically engineering them with pluripotency factors, the cells are reprogrammed into embryonic-like stem cells that have the ability to differentiate into other disease-relevant cell types like neurons or blood cells. However, iPSC-derived cells are immature and they can take months to become functional. Consequently, their slow maturation process causes iPSC-derived cells to be too young to effectively model diseases that emerge later in life.

To overcome this hurdle, Studer’s team exposed iPSC-derived skin cells and neurons that originated from both young and old donors, to a protein called “progerin.” Progerin is a mutant form of the nuclear lamin proteins that provide structure to the nuclear membrane. Mutations in these proteins cause premature aging and an early death from old age. Short-term exposure of these iPSC-derived cells to progerin caused them to manifest age-associated markers that are normally present in older cells.

Then Studer and others used iPSC technology to reprogram skin cells taken from patients with Parkinson’s disease and differentiated them into dopaminergic neurons; the type of neuron that is defective in these patients. After exposure to progerin, these cultured neurons recapitulated disease-related features, including neuronal degeneration and cell death as well as mitochondrial defects.

“We could observe novel disease-related phenotypes that could not be modeled in previous efforts of studying Parkinson’s disease in a dish,” says first author Justine Miller of the Sloan-Kettering Institute for Cancer Research. “We hope that the strategy will enable mechanistic studies that could explain why a disease is late-onset. We also think that it could enable a more relevant screening platform to develop new drugs that treat late-onset diseases and prevent degeneration.”