The broad, long-term objective of this proposal is to identify angiogenic pathways that are involved in selective mobilization and recruitment of bone marrow (BM)-derived endothelial and hematopoietic stem and progenitor cells thereby dictating heterogeneity of organ-specific vasculature. In particular, we plan to determine the mechanism by which the expression of Vascular Endothelial Growth Factor-receptors, VEGFR2 (Flk-1, KDR), VEGFR1 (Flt-1) and VEGFR3 (Flt-4) orchestrate proliferation, mobilization and incorporation of BM-derived progenitors into organ-specific neo-vasculature during regenerating processes, including lung regeneration and BM hemangiogenic reconstitution. We have shown that VEGF family of angiogenic factors promote recruitment of CD133+VEGFR2+ endothelial progenitor cells (EPCs) from BM to the angiogenic neo-vessels. We have also demonstrated that functional VEGFR1 is expressed on the subsets of hematopoietic stem and progenitors cells (HSPCs) supporting mobilization of these cells from BM. Co-recruitment of angio-competent VEGFR1+HSPCs to the neo-angiogenic vessels facilitate incorporation of VEGFR2+EPCs into functional neo-vessels. Mobilization of BM-derived progenitor cellsl is a dynamic process and requires recruitment of these cells from unique BM niches. Angiogenic factors, induce expression of metalloproteinase-9 (MMP-9), which in turn promote the release of soluble Kit-ligand (sKitL). Increase in bio-available sKitL enhance cycling and proliferation of HSPCs, setting up the stage for mobilization to the circulation. BM also contains a population of CD133+VEGFR3+ lymphatic EPCs that could possibly contribute to lymphangiogenesis. Based on these studies, we hypothesize that regenerating lung and BM provide for a pro-hemangiogenic microenvironment that is permissive for recruitment and incorporation of angio-competent BM-derived progenitors. Organ-specific angiogenic factors promote mobilization and recruitment of VEGFR2+ and VEGFR3+ EPCs to the neo-vessels. Co-recruitment of the VEGFR1+ hematopoietic cells facilitate functional incorporation of vascular progenitors and dictate vascular heterogeneity in the initial phases of organ regeneration. This hypothesis through studying the following specific aims: We plan to determine temporal, spatial and regional recruitment patterns of BM-derived progenitors during tissue revascularization-remodeling and compare their incorporation pattern in transgenic mice with diminished hemangiogenic potential including, VEGF164/164, VEGF189/189, PIGF-/-, and Id1+/-Id3-/- mice. Define the role of VEGFR1, VEGFR2 and VEGFR3 signaling in the regulation of mobilization, homing and recruitment of progenitors to the pulmonary and BM vasculature. Assess the physiological significance and contribution of BM-derived CD133+VEGFR2+, CD133+VEGFR3+EPCs and VEGFR1+HSPCs to revascularization during organ regeneration. These studies will lay the foundation for using BM-marrow derived cells for therapeutic cell therapy to enhance organ (i.e. lung, marrow) revascularization.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075234-03
Application #
6941319
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S1))
Program Officer
Goldman, Stephen
Project Start
2003-09-30
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2005
Total Cost
$336,000
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Rabbany, Sina Y; James, Daylon; Rafii, Shahin (2010) New dimensions in vascular engineering: opportunities for cancer biology. Tissue Eng Part A 16:2157-9
Rafii, Shahin; Nolan, Daniel (2010) Cholesterol activates vascular niche and hematopoiesis. Blood 115:3857-8
Yamamoto, Masaya; James, Daylon; Li, Hui et al. (2010) Generation of stable co-cultures of vascular cells in a honeycomb alginate scaffold. Tissue Eng Part A 16:299-308
Butler, Jason M; Kobayashi, Hideki; Rafii, Shahin (2010) Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer 10:138-46
Butler, Jason M; Nolan, Daniel J; Vertes, Eva L et al. (2010) Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell 6:251-64
James, Daylon; Nam, Hyung-song; Seandel, Marco et al. (2010) Expansion and maintenance of human embryonic stem cell-derived endothelial cells by TGFbeta inhibition is Id1 dependent. Nat Biotechnol 28:161-6
Kobayashi, Hideki; Butler, Jason M; O'Donnell, Rebekah et al. (2010) Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nat Cell Biol 12:1046-56
Hooper, Andrea T; Shmelkov, Sergey V; Gupta, Sunny et al. (2009) Angiomodulin is a specific marker of vasculature and regulates vascular endothelial growth factor-A-dependent neoangiogenesis. Circ Res 105:201-8
Kopp, Hans-Georg; Hooper, Andrea T; Avecilla, Scott T et al. (2009) Functional heterogeneity of the bone marrow vascular niche. Ann N Y Acad Sci 1176:47-54
Hooper, Andrea T; Butler, Jason M; Nolan, Daniel J et al. (2009) Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells. Cell Stem Cell 4:263-74

Showing the most recent 10 out of 29 publications