HSCI Science Update: April 2011

April 6, 2011

Not Just a Cushion: An Active Role for the Cerebrospinal Fluid

The cerebral cortex is the thin layer of nerve cells covering the brain, immediately adjacent to the cerebrospinal fluid (CSF) in which it floats. This cushioning fluid provides mechanical and immunological protection to the brain inside the hard skull. But recent work from Harvard Stem Cell Institute Principal Faculty Member Christopher Walsh and colleagues demonstrates that the CSF has a more active role than simply being a pillow for the brain; it also contains a library of proteins important to neuronal development throughout life. These CSF proteins work together with neuronal surface proteins to promote stem cell proliferation. In particular, levels of the extracellular protein Igf2 are significantly increased during both embryonic development and cancerous states. With this information, researchers may now be able to tune the CSF protein composition to regulate stem cell behavior in health and disease. It also provides a potential model for other cells that develop in relation to extracellular fluids, such as the lung, gut, and vascular linings.

Lehtinen, M.; Zappaterra, M.; Chen, X.; Yang, Y.; Hill, A.; Lun, M.; Maynard, T.; Gonzalez, D.; Kim, S.; Ye, P.; D'Ercole, A.; Wong, E.; LaMantia, A.; and Walsh, C. (2011) The Cerebrospinal Fluid Provides a Proliferative Niche for Neuronal Progenitor Cells. Neuron 893-905.

Better Blood: A New Model for Studying Hematopoietic Stem Cells

Long-term hematopoietic stem cells (HSCs) have the ability to give rise to all of the blood cell types in an animal over its entire lifetime. Short-term HSCs, on the other hand, are only capable of self-renewing immediately following a destructive event. For these reasons, long term HSCs are the more valuable population when considering blood transplants. Zebrafish have long been recognized as a model system for studying developmental biology, but the first successful HSC transplants were reported just a few years ago. This early research looked only at short-term HSC repopulation, leaving long term repopulation (LTR) assays significantly underdeveloped. Recent work by HSCI Executive Committee chair Leonard Zon offers a reliable LTR assay to the field. Zon's team first identified the location of a set of genes responsible for immune-resistance in zebrafish DNA, allowing researchers to match donors and recipients based on their immuno-compatibility and reducing the potential for transplant rejection. Additionally, the team developed the specific conditions necessary for successful long-term repopulation studies, including a method for delivering precise numbers of donor cells and a statistical model to predict the long-term repopulation potential for any cell in the marrow. The work will advance all future zebrafish HSC experiments, which model human diseases such as bone marrow failure and hematopoietic cancers.

De Jong, J.; Burns, C.; Chen, A.; Pugach, E.; Mayhall, E.; Smith, A.; Feldman, H,; Zhou, Y,; Zon, L. (2011) Characterization of Immune-Matched Transplantation in Zebrafish. Blood. Feb 23. [Epub ahead of print]

To Grow or Not to Grow

Tissues know when to stop growing thanks to a cellular signaling pathway appropriately called "Hippo," whose dysfunction results in enormous, oversized tumors. Hippo regulates tissue size by limiting cell proliferation and promoting cell death through a series of molecular "conversations" inside the cell. While the pathway itself is rather well defined, the extracellular signals that moderate its activity have been a mystery. Recent work from HSCI Principal faculty member, Fernando Camargo and Affiliate faculty member Jan Pruszak, reveals an upstream regulator of one essential Hippo protein: Yap1 (or Yes-Associated Protein). The researchers show that Yap1's location within the cell helps determine tissue growth and that its location is directly linked to an extracellular "crowd control" protein called α-catenin, which was previously thought to be a simple structural linker between cells. When α-catenin levels are low, Yap1 becomes activated and localizes to the cell's nucleus. This triggers stem cell proliferation and growth. But when cells become overcrowded, α-catenin levels increase thereby inactivating Yap1 and shutting down growth. This model is supported by the fact that in many epithelial cancers, α-catenin is absent or mutated. Knowing the mechanism of this growth "switch" may allow researchers to artificially grow skin cells when needed and conversely shut down growth in some cancerous states. More generally, understanding this protein and pathway will help us understand how organ growth and size are regulated.

Schlegelmilch, K.; Mohseni, M.; Kirak, O.; Pruszak, J.; Rodriguez, J.; Zhou, D.; Kreger, B.; Vasioukhin, V.; Avruch, J.; Brummelkamp, T.; Camargo, F. (2011) Yap1 Acts Downstream of α-Catenin to Control Epidermal Proliferation. Cell 782-95.