Biology Reference
In-Depth Information
genetic predispositions. In some cases, developmental blocks lead to defi-
ciencies in certain blood cell populations such as RBCs, in the case of
anemia, or white blood cells, resulting in immunodeficiency. Alternatively,
when excess production of blood cells occurs, it typically involves a single
lineage. For instance, some myeloproliferative disorders (MPDs) can be
characterized by increases in myeloid cells of the GM lineage. In both of
these cases (developmental blocks and enhanced proliferation), hemato-
poietic malignancies can arise. Alternatively, when inappropriate develop-
ment of lymphocytes takes place, inflammatory responses against self-tissues
can ensue, leading to debilitating autoimmunity. miRNAs have been
connected to all of these disorders owing to their critical roles in regulating
blood cell development.
5.1. Inflammatory hematopoiesis
A majority of our understanding of mammalian hematopoiesis is based upon
animal experiments that have been performed under steady-state, nonin-
flammatory conditions. However, mammals are regularly exposed to a
variety of stress conditions that have a clear impact on blood cell develop-
ment, including microbial infection. The resulting inflammatory response
produces cytokines and growth factors with the propensity to impact
hematopoietic development resulting in “inflammatory hematopoiesis”
(
Fig. 6.2
B). Mouse models have revealed an enhanced output of GM
populations and a concurrent reduction in B lymphocytes and erythroid
precursors under such conditions (
O'Connell
et al
., 2008
;
Ueda
et al
., 2005
).
In conjunction with host-produced growth factors, this acute developmen-
tal shift also appears to be influenced by direct recognition of pathogen-
associated molecular patterns by stem and progenitor populations (
Nagai
et al
., 2006
;
O'Connell
et al
., 2008
;
Takizawa
et al
., 2011
;
Ueda
et al
., 2005
).
Cells that make up the stem and progenitor compartment have recently
been shown to express Toll-like receptors which can directly impact the
expression of miRNAs among other genes (
O'Connell
et al
., 2007, 2008
;
O'Neill
et al
., 2011
).
A number of recent studies have provided evidence that specific miR-
NAs may be linked to inflammatory hematopoiesis. miR-155 is upregulated
in the bone marrow compartment in response to inflammatory stimuli, and
its overexpression triggers a myeloid phenotype resembling that caused by
treatment with endotoxin (
O'Connell
et al
., 2008
). Although transcription
of BIC (the precursor to miR-155) is controlled by NF-
B and JNK
(
O'Connell
et al
., 2007
;
Thai
et al
., 2007
), a recent report found that
Hoxa9, which is expressed in stem and progenitor cells, also regulates
miR-155 levels (
Hu
et al
., 2010
). miR-146a is also upregulated by
inflammatory signaling pathways and has the opposite impact on hemato-
poiesis. miR-146a
k
/
mice develop an MPD characteristic of chronic
