Gillian May

Transcription factor‐mediated lineage switching reveals plasticity in primary committed progenitor cells

The developmental plasticity of transplanted adult stem cells challenges the notion that tissue‐restricted stem cells have stringently limited lineage potential and prompts a re‐evaluation of the stability of lineage commitment. Transformed cell systems are inappropriate for such studies, since transformation potentially dysregulates the processes governing lineage commitment. We have therefore assessed the stability of normal lineage commitment in primary adult haematopoietic cells. For these studies we have used prospectively isolated primary bipotent progenitors, which normally display only neutrophil and monocyte differentiation in vitro. In response to ectopic transcription factor expression, these neutrophil/monocyte progenitors were reprogrammed to take on erythroid, eosinophil and basophil‐like cell fates, with the resultant colonies resembling the mixed lineage colonies normally generated by multipotential progenitors. Clone‐marking and daughter cell experiments identified lineage switching rather than differential cell selection as the mechanism of altered lineage output. These results demonstrate that the cell type‐specific programming of apparently committed primary progenitors is not irrevocably fixed, but may be radically re‐specified in response to a single transcriptional regulator.

Inference, Validation, and Dynamic Modeling of Transcription Networks in Multipotent Hematopoietic Cells

Abstract:  Identifying the transcription factor interactions that are responsible for cell‐specific gene expression programs is key to understanding the regulation of cell behaviors, such as self‐renewal, proliferation, differentiation, and death. The rapidly increasing availability of microarray‐derived global gene expression data sets, coupled with genome sequence information from multiple species, has driven the development of computational methods to reverse engineer and dynamically model genetic regulatory networks. An understanding of the architecture and behavior of transcriptional networks should lend insight into how the huge number of potential gene expression programs is constrained and facilitates efforts to direct or redirect cell fate.

7 – The Genetic Regulation of Stem Cell Fate

This chapter reviews transcriptional programs of stem cells with a particular, although not exclusive, emphasis on stem and progenitor cells of the hemopoietic system. In the context of transplantation, stem cell definitions are more stringent and the standard used is the ability to reconstitute an entire tissue system and maintain it for an extended period, and preferably, for the lifetime of the organism. Stem cells in adult muscle may function in repair, as may stem cells in the liver, kidney, pancreas, and the central nervous system. These cells, derived from the inner cell mass of in vitro fertilization (IVF) embryos surplus to requirements exhibit pluripotent differentiation in vitro. A classic early example of this type is the so-called brains to blood study in which neurosphere-derived neural stem cells (NSCs) were reported to contribute to hemopoiesis in a murine transplantation model thereby crossing not only tissue but also germ layer boundaries.