Lab Overview
Our laboratory is interested in physiologically relevant
and clinically important angiogenesis. We have explored the role
of integrin-mediated pathways in angiogenesis and neovascular
eye diseases and have also studied a number of other angiostatic
molecules including fragments of tRNA synthetases and matrix
metalloproteinases. Recently, we have combined angiostatic monotherapies
targeting different aspects of angiogenesis and demonstrated
that such combination angiostatic therapy is synergistic. We
have observed that adult bone marrow derived endothelial and
myeloid progenitor cells target activated astrocytes/glia in
the eye and that these progenitor cells exert profound vasculo-
and neurotrophic effects that can prevent vascular and neuronal
degeneration associated with inherited retinal degenerations
and hypoxia-induced vascular pathology. We have further characterized
the molecular basis for stem cell homing to sites of angiogenesis
in the eye, defined the neurotrophic effect in retinal degenerations
and used these cells to deliver static and/or trophic drugs to
sites of ocular pathology. Our work has provided an experimental
platform on which to build a better understanding of cell-cell
interactions during normal and pathological angiogenesis and
is being translated into the clinics as cell based therapies
for neovascular and degenerative eye disease.
Highlight
Ritter, M., Banin, E., Aguilar, E.A., Dorrell, M.I. Moreno S.K. and M. Friedlander
(2006). Myeloid progenitors differentiate into microglia and promote vascular
repair in a model of ischemic retinopathy. Journal of Clinical Investigation.
116:3266-3276.
During the course of our investigations with bone marrow derived HSC, we noticed
that not all surviving, targeted cells injected into the eye were incorporated
into the blood vessels themselves; a significant number of injected, surviving
cells were observed to target the vasculature and remain perivascular in location.
In an attempt to better characterize the injected cells and to also develop a
positive selection (rather than depletion) process for obtaining these cells,
we determined that most of the Lin- HSC were also highly positive for CD44, the
hyaluronic acid receptor. In this paper we further characterize this population
of adult bone marrow derived cells, demonstrating that many of these cells are
myeloid progenitors. Most significantly, we determined that these cells display
myeloid progenitor markers upon entering the eye, but, rapidly differentiate
into microglia, up-regulating surface markers characteristic of these cells.
Using selective microglial depletion with clodronate liposomes, as well as bone
marrow from cre mice in which HIF-1? was selectively deleted from myeloid cells,
we confirmed a role for these cells and HIF-1? in regulating the angiogenic response
to hypoxia in a mouse model of ischemic retinopathy. This study not only provides
a broader base for proceeding to the clinics with cell-based therapy of ischemic
vascular disease, but also demonstrates, for the first time, a role for microglia
in regulating retinal neovascular responses.
2006 Publications
Ritter, M., Banin, E., Aguilar, E.A., Dorrell, M.I. Moreno S.K. and M. Friedlander
(2006). Myeloid progenitors differentiate into microglia and promote vascular
repair in a model of ischemic retinopathy. J. Clin. Invest. 116:3266-3276.
Banin, E., Dorrell, M.I., Aguilar, E., Ritter, M.R.,Aderman, C.M., Smith, A.C.H.,
Friedlander, J., and M. Friedlander. (2006). T2-TrpRS inhibits pre-retinal
neovascularization and enhances physiological vascular regrowth in oxygen-induced
retinopathy as assessed by a new method of quantification. Invest. Ophthal.
Vis. Sci., 47(5):2125-34.
Ritter, M., Reinisch, J., Friedlander, S.F., and Friedlander, M. (2006). Myeloid
Cells in Infantile Hemangioma and a Possible Surrogate Model. Amer. J. Path.
168: 621-628.
Jin, H., Aiyer, A., Su, J., Borgstrom, P., Stupack, D., Friedlander, M. and
Varner, J. (2006). A homing mechanism for bone marrow derived progenitor cell
recruitment to the neovasculature. J. Clin. Invest., 116(3):652-62.
Dorrell, M.I. and Friedlander, M. (2006). Cell guidance in retinal angiogenesis.
Progress in Retinal and Eye Research. 25(3):277-95.
Ritter, M. and Friedlander, M. (2006). Integrins in Ocular Angiogenesis. In
Ocular Angiogenesis (J. Tobran-Tink and C. Barnstable, eds.), pp 279-290. Humana
Press. Totowa, NJ.
