From: HSCI [mailto:[log in to unmask]] On Behalf Of
HSCI
Sent: April 07, 2011 09:56
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Subject: HSCI SCIENCE UPDATE
Harvard Stem Cell Institute Science Update
Highlights from Selected Projects
April 2011
The diverse expertise of HSCI faculty is represented in a range of
publications each month, typifying the broad range of approaches HSCI is
taking toward advancing stem cell biology. Below is a sampling.
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 á-catenin, which was previously thought to be a simple structural
linker between cells. When á-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, á-catenin levels increase
thereby inactivating Yap1 and shutting down growth. This model is supported
by the fact that in many epithelial cancers, á-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 á-Catenin to Control Epidermal Proliferation.
Cell 782-95.
To support this and other exciting research at HSCI, please click here.
To learn more about HSCI, please visit www.hsci.harvard.edu.
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