Mount Sinai Hospital researchers discover new insights into genesis of stem cells

Discovery will advance stem cell technologies worldwide and promote the development of new regenerative medicines

Mount Sinai Hospital researchers including Drs. Andras Nagy and Jeff Wrana have discovered new insights into the genesis of stem cells, which will improve the efficiency of stem cell creation for use in tissue regeneration and in the development of new drugs.

The study was published today in the leading biomedical journal Cell Stem Cell.

The goal of the study was to explore the process of changing fully mature cells of the body (known as somatic cells) into a pluripotent state (i.e., cells that can develop into most other cell types), and understand the molecular and genetic changes that occur during the cells' reprogramming. Understanding this process will help researchers identify limitations in making induced pluripotent stem (iPS) cells, which are a source of great hope for use in regenerative medicine, as well as in the development of new drugs to prevent and treat various diseases.

"Using genomic technologies, we pried open the black box of reprogramming, gaining new insight into how to make induced pluripotent stem cells faster and more efficiently," said Payman Samavarchi-Tehrani, a PhD candidate student in Dr. Wrana's lab.

The study represents the first research project worldwide aimed at systematically mapping the molecular events underlying a cell's transition from a somatic state to one with pluripotent ability.

Previous attempts to understand cellular reprogramming have been typically hindered by inefficient methods of analyzing the process. In the present study, the Lunenfeld team assessed the expression pattern of thousands of genes within the genome of mice (a model system that can be applied to studies of human illnesses), and looked at how these patterns changed during the reprogramming of fibroblast cells (i.e., connective tissue cells) generated in Dr. Nagy's lab. Using this approach, the researchers uncovered a number of genes and cellular signaling (communication) pathways that change over time, which led to the hypothesis that, through manipulation of these genes, they could improve the efficiency and speed of reprogramming.

The Lunenfeld team also conducted RNA interference screening (or RNAi, a relatively new technique that helps researchers assess the function of proteins and genes) by utilizing the Institute's leading-edge robotics facility pioneered by Dr. Wrana. The robotics technology enables researchers at Mount Sinai Hospital and others in Ontario's biomedical community to analyze the function of thousands of genes at a time, and rapidly identify the properties and processes important in human diseases.

"Through the use of high-throughput screening and gene expression profiling, we can gain significant insight into the underlying mechanisms of stem cell biology," said Samavarchi-Tehrani.

The researchers found that the reprogramming process is comprised of three pivotal phases termed initiation, maturation, and stabilization. They also discovered a cellular signaling pathway that plays a critical role in the initiation phase. The pathway - mediated by a protein called BMP - enhances the reprogramming process and kick-starts the initiation phase.

"This is the first time it's been shown that activating the BMP pathway enhances reprogramming through induction of molecular and morphological changes," said Azadeh Golipour, a graduate student in Dr. Wrana's lab. "Increasing the efficiency of the reprogramming process gives us new insights into the biology of iPS cells, and brings us one step closer to developing new methods in regenerative medicine."

The findings are the first step in a new stem cell project begun earlier this year by Drs. Nagy and Wrana. In March 2009, Dr. Nagy discovered a new method to create pluripotent stem cells without disrupting healthy genes. Dr. Nagy's method uses a novel wrapping procedure to deliver specific genes to reprogram cells into stem cells. Previous approaches required the use of viruses to deliver the required genes, a method that may damage the DNA. Dr. Nagy's method does not require viruses, and so overcomes a major hurdle for the future of safe, personalized stem cell therapies in humans.