HSCI Science Update: September 2010

October 13, 2010

Synthetic RNAs Leading to Real Changes in Reprogramming Strategies

Key limiting factors in the utility and applicability of induced pluripotent stem cells (IPSCs) include the low efficiency of transformation and the potentially oncogenic factors that are used in the protocols. An exciting advance recently published by Harvard Stem Cell Institute Principal Faculty member Derrick Rossi and colleagues is now likely to remove both these obstacles. In their new paper, Rossi and fellow researchers describe a reprogramming strategy that uses synthetic mRNAS to reprogram cells to pluripotency and differentiate pluripotent cells toward clinically useful cell types.  This safer and more efficient approach for reprogramming and directed differentiation represents a promising advance toward creating a more reliable cell source for both research purposes and regenerative cell-based therapies.

Warren, L., Manos, P.D., Ahfeldt, T., Loh, Y.H., Li, H., Lau, F., Ebina, W., Mandal, P.K., Smith, Z.D., Meissner, A., Daley, G.Q., Brack, A.S., Collins, J.J., Cowan, C., Schlaeger, T.M., Rossi, D.J. (2010). Highly Efficient Reprogramming to Pluripotency and Directed Differentiation of Human Cells with Synthetic Modified mRNA. Cell Stem Cell. Sep 29. [Epub ahead of print]

MicroRNAs Jump into the Stem Cell Regulation Pool

MicroRNAs have been previously shown to be involved in blood cell differentiation but their effect on the state of stem cells has not been well understood. Recent findings by David Scadden, Scientific co-director of HSCI, and colleagues show that the microRNA processing enzyme, Dicer, is required for the persistence of stem cells and a specific microRNA, miR-125a, has an important role in regulating the size of the stem cell population. These findings shed light on yet another role for microRNAs, here in controlling the size of the stem cell pool, and provide another potential means by which to manipulate stem cell numbers to provide a cell source for potential therapies.

Guo, S., Lu, J., Schlanger, R., Zhang, H., Wang, J.Y., Fox, M.C., Purton, L.E., Fleming, H.H., Cobb, B., Merkenschlager, M., Golub, T.R., Scadden, D.T. (2010). MicroRNA miR-125a controls hematopoietic stem cell number.
Proc Natl Acad Sci U S A. 107, 14229-34.

mTORC1 and Plzf, Disraeli and Gladstone of the Germline Progenitor Pool

Maintenance of stem cell pools is a complex control problem and the factors regulating it are not yet entirely understood.  HSCI Principal Faculty member Piers Pandolfi and colleagues recently made significant progress toward understanding the spermatogonial progenitor cell population within the germline stem cell ppol. The researchers identify how a factor called mTORC1 leads to stem cell depletion to the degree to which it is not opposed by another factor called Plzf. This mechanistic elaboration reveals a delicate balance between these two factors required for maintaining the germline stem cell pool.  These findings may extend to other stem cell pools and have important implications for our ability to regulate stem cell number toward therapeutic goals.

Hobbs, R.M., Seandel, M., Falciatori, I., Rafii, S., Pandolfi, P.P. (2010). Plzf Regulates Germline Progenitor Self-Renewal by Opposing mTORC1. Cell 142, 468-479.