Note: These accounts of talks given at ISSCR were written by Andrea Ditadi.
Yann Barrandon: Thymus cells make skin, hair follicles
The skin, vagina, cornea, esophagus and other organs in contact with external environment, no matter their germ layer of origin, are all covered with stratified epithelium. Such epithelium is characterized by cells that undergo constant self-renewal. Yann Barrandon of Lausanne University Medical School reported some years ago that this long-term renewal was due to a population of multipotent, clonogenic stem cells. (Claudinot et al 2005, PNAS). These cells persist in niches and proliferate according to environmental cues. In vitro, these stem cells form colonies that can be serially cultured and transplanted. They can also generate all epithelial structures, including the hair follicle and sebaceous gland. Cells from the stratified epithelium of different tissues express a common pattern of genes. The thymic epithelium, which does not come into contact with the external environment, is not as well studied.
Reports that the cell-cycle regulator p63 is required for both stratified and thymic epithelium to develop suggested that they may share a similar progenitor. When Barrandon focused his attention on thymic epithelial cells (TEC), he found a subpopulation of rat TEC (0.1-0.5%) that are clonogenic and can be serially passaged. Those TEC progenitors can be recovered from both embryonic and postnatal thymuses.
In contrast to progenitors in stratified epithelium, cultured clonogenic progenitors generally maintain their “thymus identity” but also express epithelial/hair markers. Barrandon combined epithelial cells from both skin and thymus and transplanted these under the kidney capsules in immunodeficient mice. However, while epithelial progenitors cannot contribute to thymus development, thymic TEC progenitors can form thymus as well as skin and even complex skin structures like hair follicles.
In a serial transplantation experiment, recovered TEC progenitors from secondary recipients retain a thymic “signature” expressing almost all the ordinary thymic genes. All the results Barrandon showed suggest that thymic epithelium may contain a very immature multipotent epithelial progenitor with a broader spectrum of potential than epithelial stem cells. And it can be speculated that thymic and stratified epithelia derive from the same precursor, even though their position and function are totally different. In any case, understanding how the skin forms complex structures could lead to improvements in skin grafts and treatments for other skin diseases.
Lausanne University Medical School and Ecole Polytechnique Fédérale Lausanne
IMPACT OF MICROENVIRONMENTAL CHANGES ON EPITHELIAL STEM CELL FATE
Plenary 36. Growth Control in Stem Cells and Cancer Plenary V
Getting HSCs started with transcription factor SCL
Gereige Laurraine, a student in Hanna Mikkola’s lab at UCLA brings new light on the function of SCL/Tal1, a well known transcription factor required for hematopoiesis. Though mouse embryos lacking the gene for SCL die 9.5 days postconception for lack of blood cells, SCL appears dispensable thereafter for hematopoietic stem cell (HSC) development and function.
Laurraine first used ES cells to create hemangioblasts, precursors of both hematopoietic and endothelial cells. To discover which genes SCL targets, she performed Chip-on-chip analyses to compare cells that both expressed and lacked the SCL gene. These analyses indicated that SCL plays a dual role: it activates major hematopoietic transcription factors that promote the development and maintenance of HSC, and it represses transcription factors critical for the specification of other mesodermal fates. (More specifically, SCL activates factors including Gata2, C-myb, Fli1, Lyl1, Tel, Gfi1, Sox17, and represses factors including those that promote cardiac lineages [Gata4, Tbx20] as well as mesenchymal lineages [Foxf1a, PDGF-R-alpha].) Analysis of the acetylation and methylation of candidate SCL target genes in the ES-cell derived hemangioblasts confirmed the activation of hematopoietic genes and the repression of alternative mesodermal ones.
Laurraine was able to abolish SCL expression at a later point in development (She used a Cre-lox system tied to the expression of hematopoietic marker vav). She showed that the number of adult HSC (isolated as murine Lin- ckit+ bone marrow cells) was not affected, and that other HSC genes like Lyl1, Gfi1, C-myb were still expressed even in the absence of SCL. Her results confirm that, once hematopoietic specification occurs, the SCL-induced hematopoietic program is stable even without SCL.
In addition, Laurraine suggested that Lyl1, a factor in the same family as SCL, may maintain the hematopoietic program in the absence of SCL. Indeed, contemporary absence of Lyl1 and SCL leads to a complete absence of HSC. In the model she proposes, SCL plays a major role in the emergence of HSC before E10.5, Lyl1 maintains the SCL induced transcriptional program in HSC/progenitors until birth, and both can maintain the cells after birth.
Gereige Laurraine, UCLA, Los Angeles, CA, USA,
SPECIFICATION AND MAINTENANCE OF THE SCL INDUCED HEMATOPOIETIC STEM CELL FATE
Concurrent 42. Concurrent Session IIB: Stem Cell Fate Choice
These accounts are by Andrea Ditadi, a postdoctoral fellow studying stem cells at Hopital Necker – Enfants Malades in Paris.
Note from Niche editor This post comes as a response to my solicitation in June calling for people to submit their accounts of ISSCR 2009. I’d asked people to describe what most interested them and to disclose any conflicts of interest. I’m very grateful for these volunteers’ help making more information available.