Year 1

Induced pluripotent stem cells (iPSCs) hold great promise in regenerative medicine: these cells are similar to embryonic stem cells (ESCs) but can be derived upon “reprogramming” of any mature cell type isolated from a patient. Thus, tissue-specific stem cells derived from iPSCs and re-injected into the same patient may not trigger immune rejection. However, before the full potential of iPSCs is achieved, we need to learn how to better generate these cells, control their maturation into tissue-specific stem cells and progenitors, and harness their tumorigenic potential. Interestingly, ESCs and iPSCs share many characteristics of cancer cells, including their unlimited proliferation potential, and emerging evidence suggests that the mechanisms underlying the infinite proliferation of cancer cells and ESCs are intimately intertwined. Similarly, the progressions stages of tumorigenesis and cellular reprogramming to iPSCs share several characteristics, including changes in the packaging of the chromosomes.

Based on these observations, we proposed to directly study the function of a major cancer pathway, the RB pathway, in cellular reprogramming and iPSCs. RB is a key tumor suppressor in humans. RB acts as a cellular brake that restricts cell division but has several other cellular functions, including in the control of cellular maturation. When RB is mutated, cells divide faster and become more immature, two features of cancer cells, but also of cells undergoing reprogramming. We hypothesized that RB is an important regulator of cellular reprogramming and will test this idea using mouse and human cell types in culture. In the last year, we have performed experiments that largely support this hypothesis. We have found that, similar to its role in normal cell cycle, RB acts as a brake to normally restrict the reprogramming of cells into iPSCs. We have also found that RB is regulated in cells by enzymes that normally control the coating structure of chromosomes; these enzymes are thought to play a role in reprogramming, suggesting that RB may be a critical regulator of reprogramming by controlling the ability of reprogramming factors to modify the structure of the DNA. These experiments now provide a powerful system to analyze the molecular mechanisms underlying cellular reprogramming.