Summary of Research Project Results under JSPS FY2003
"Research for the Future Program"

1.Research Institution Kyoto University
2.Research Area Life Sciences
3.Research Field Angiogenesis and Vascular Development Control
4.Term of Project FY 1999 - FY 2003
5.Project Number 99L01301
6.Title of Project The Functions of Chemokines in Blood Vessel Formation

7.Project Leader
Name Institution,Department Title of Position
Takashi, Nagasawa Kyoto University,Institute for Frontier Medical Sciences Professor

8.Core Members
Names Institution,Department Title of Position

9.Summary of Research Results
Mechanisms regulating blood vessel formation during organ development remain poorly understood. We have found a novel mode of organ vascularization. In the developing small intestine, many interconnecting vessels form between larger superior mesenteric artery (SMA) and the neighboring intrinsic primary capillary plexus surrounding the primitive gut and they elongate. CXCR4 is specifically expressed in arteries in the mesenteries and mice lacking CXC chemokine ligand (CXCL)12 lack the interconnecting vessels and CXCR4 expression in SMA. Mice in which CXCR4 is specifically deleted in the endothelium reveal vascular defects identical to those observed in the conventional CXCR4-/- embryos. Therefore, CXCL12 acts on endothelial cells to up-regulate CXCR4 and mediates the connection between the larger artery and neighboring intrinsic capillary plexus in an organ-specific manner.
We have identified the earliest B cell precursors in fetal liver and have shown that these precursors require CXC chemokine ligand (CXCL)12.
We have shown that colonization of bone marrow by hematopoietic stem cells (HSCs) is severely impaired in CXCL12-/- embryos. Enforced expression of CXCL12 under the control of vascular-specific Tie-2 regulatory sequences could completely rescue the reduction of HSCs in CXCL12-/- bone marrow. CXCL12 was detected in the vicinity of the vascular endothelial cells in bone marrow. CXCL12 plays a critical role in colonization of bone marrow by HSCs.
Primordial germ cells (PGCs) migrate through the tissues of the embryos and colonize the gonads during development. We have shown that, in CXCL12-/- mice, PGCs undergo directed migration through tissues of embryos but the numbers of PGCs in the gonads are significantly reduced. These findings reveal the essential role for CXCL12 in murine PGC development likely by controlling colonization of the gonads by PGCs.

10.Key Words
(1)development (2)immunology (3)chemokine
(4)angiogenesis (5)hematopoiesis