This application addresses broad Challenge Area (11) Regenerative Medicine and specific Challenge Topic, 11-HL-101* Develop cell-based therapies for cardiovascular, lung, and blood diseases. Given their self-renewing and pluripotent nature, human embryonic stem (hES) and induced pluripotent stem (iPS) cells hold great promise as cell replacement therapy and regenerative medicine. We recently developed a 2D culture system for differentiating hES cells into the endothelial lineage, and demonstrated that hES cell-derived endothelial cells (hES-EC) can self-assemble into functional blood vessels that spontaneously integrate into the circulatory system after transplantation into immunodeficient mice. However, a key challenge for clinical translation of hES-EC-based therapies is the immunological rejection. The major goal of this project is to mechanistically understand the immunological responses to allogeneic hES-EC, and to develop effective approaches to preventing the rejection of hES cell-derived endothelial allografts. A key factor currently impeding the study of the immunogenicity and allogenicity of hES/iPS cells and their derivatives is the lack of a suitable in vivo model. We have developed a novel protocol for human immune reconstitution in immunodeficient mice. The humanized mice (hu-mice) exhibit sustained repopulation with multilineages of human lymphohematopoietic cells and formation of secondary lymphoid organs, develop strong antigen-specific human T cell and antibody responses upon immunization, and mediate transplant rejection. In this proposal, we will use this hu-mouse model to pursue the following two specific aims.
In Aim 1, we will examine the allogenicity of hES-EC in hu-mice. The goal of this aim is to understand the allogenicity of hES-EC and determine whether hES-EC at different differentiation stages (e.g., early vs. late hES-EC) differ in allogenicity. First, we will determine the allogenicity of hES-EC using a series of in vitro assays. We will then assess in vivo immune responses to allogeneic hES-EC in hu-mice. We will also assess the survival/rejection of hES-EC allografts in hu-mice that are depleted of human T cells or T cell subset(s) for identifying the immune components that are essential to hES-EC allograft rejection.
In Aim 2, we will explore the possibility of inducing tolerance to hES-EC allografts in hu-mice through establishment of mixed hematopoietic chimerism. We will develop protocols for in vitro differentiation of transplantable hematopoietic stem/progenitor cells from hES cells, and with these cells to induce chimerism and donor-specific tolerance in hu-mice. These studies will determine whether hES-EC derived from the same hES cell line that is used for establishing hematopoietic chimerism can be permanently accepted by the chimeric hu-mice without the need of immunosuppression. Successful completion of the proposed studies will help us to understand the mechanisms of alloimmune responses to hES-EC and develop effective strategies to overcome the immunological hurdle to hES cell-based regenerative medicine.

Public Health Relevance

Immunological rejection is a key challenge for clinical translation of human embryonic stem (hES) and induced pluripotent stem (iPS) cell-based regenerative medicine. This proposal aims to use a humanized mouse model to assess the allogenicity of hES cell-derived endothelial cells and to develop strategies for controlling alloimmune responses to hES cell-derived endothelial allografts.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
1RC1HL100117-01
Application #
7826527
Study Section
Special Emphasis Panel (ZRG1-BDA-A (52))
Program Officer
Thomas, John
Project Start
2010-04-21
Project End
2012-03-31
Budget Start
2010-04-21
Budget End
2012-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$895,209
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Bai, Hao; Chen, Kang; Gao, Yong-Xing et al. (2012) Bcl-xL enhances single-cell survival and expansion of human embryonic stem cells without affecting self-renewal. Stem Cell Res 8:26-37
Yang, Yanping; Wang, Hui; Yu, Hui et al. (2011) IFN-? promotes graft-versus-leukemia effects without directly interacting with leukemia cells in mice after allogeneic hematopoietic cell transplantation. Blood 118:3721-4
Hu, Zheng; Van Rooijen, Nico; Yang, Yong-Guang (2011) Macrophages prevent human red blood cell reconstitution in immunodeficient mice. Blood 118:5938-46

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