Regulated Expansion of Lympho-hematopoietic Stem and Progenitor Cells from Human Embryonic Stem Cells (hESC)

Regulated Expansion of Lympho-hematopoietic Stem and Progenitor Cells from Human Embryonic Stem Cells (hESC)

Funding Type: 
Comprehensive Grant
Grant Number: 
RC1-00108-B
Award Value: 
$1,653,416
Stem Cell Use: 
Embryonic Stem Cell
Status: 
Closed
Public Abstract: 
Statement of Benefit to California: 
Progress Report: 

Year 1

It is well recognized from adult stem cell studies that the growth of transplanted bone marrow is generated from the hematopoietic (“blood-forming”) stem and progenitor cells provided by the donor bone marrow. Mature, differentiated cells that accompany the hematopoietic stem cells, disappear rapidly after transplantation as they lack the ability to self-renew. It is thus essential when designing clinical approaches that use tissue derived from human embryonic stem cells (hESC), to specifically target the production of stem and progenitors that will survive, proliferate and differentiate normally after transplantation. We and others have shown that blood cells can be generated from hESC. However, it has become apparent more recently that the types of blood cells that hESC can produce under current conditions are more limited functionally than those found in bone marrow or cord blood. Over the past year of funding, we have studied this problem in the following ways. First, we have identified some of the key genetic differences in the way blood is formed from hESC that may be particularly important in the formation of the lymphoid cells of the immune system. Second, we have identified a very early stage of differentiation at which the pluripotent character of hESC is lost and blood forming potential is gained. We have called this primitive population the “embryonic mesoderm progenitor” (EMP) cells as they have the potential to make many if not all the cells of the mesoderm germ layer. We have developed ways to isolate the EMP cells and have begun to study how genes regulate their production from hESC. Third, we have developed a way to measure the efficiency of the process of blood formation from hESC so that we can find optimal cell lines and conditions for the process. During the next year of funding, we will continue to study the hEMP and other blood progenitors with the ultimate goal of learning how to improve production of the lymphoid immune system from hESC.

Year 2

It is well recognized from adult stem cell studies that the growth of transplanted bone marrow is generated from the hematopoietic (“blood-forming”) stem and progenitor cells provided by the donor bone marrow. Mature, differentiated cells that accompany the hematopoietic stem cells, disappear rapidly after transplantation as they lack the ability to self-renew. It is thus essential when designing clinical approaches that use tissues or cells derived from human embryonic stem cells (hESC), to specifically target the production of stem and progenitors that will survive, proliferate and differentiate normally after transplantation. We and others have shown that blood cells can be generated from hESC. However, it has become apparent more recently that the types of blood cells that hESC can produce under current conditions are more limited functionally than those found in bone marrow or cord blood. Over the past year of funding, we have studied this problem in the following ways. First, we have identified some of the key genetic differences in the way blood is formed from hESC that may be particularly important in the formation of the lymphoid cells of the immune system. Second, we have identified a very early stage of differentiation at which the pluripotent character of hESC is lost and blood forming potential is gained. We have called this primitive population “embryonic mesoderm progenitor” (EMP) cells as they have the potential to make many if not all the cells of the mesoderm germ layer. We have developed ways to isolate the EMP cells and have begun to study how genes regulate their production from hESC. Third, we have developed a way to express genes in hESC and hEMP to try and improve how these cells produce blood. During the next year of funding, we will continue to study the hEMP and other blood progenitors with the ultimate goal of learning how to improve production of the lymphoid immune system from hESC.

Year 3

It is well recognized from adult stem cell studies that the growth of transplanted bone marrow is generated from the hematopoietic (“blood-forming”) stem and progenitor cells provided by the donor bone marrow. Mature, differentiated cells that accompany the hematopoietic stem cells, disappear rapidly after transplantation as they lack the ability to self-renew. It is thus essential when designing clinical approaches that use tissue derived from human embryonic stem cells (hESC), to specifically target the production of stem and progenitors that will survive, proliferate and differentiate normally after transplantation. We and others have shown that blood cells can be generated from hESC. However, it has become apparent more recently that the types of blood cells that hESC can produce under current conditions are more limited functionally than those found in bone marrow or cord blood. Over the past year of funding, we have studied this problem in the following ways. First, we have identified some of the key genetic differences in the way blood is formed from hESC that may be particularly important in the formation of the lymphoid cells of the immune system. Second, we have carefully compared the hematopoietic capacity of six new embryonic stem cell lines developed at UCLA, to identify which are the best for blood formation. This work has been conducted as part of a collaboration with several teams at UCLA. Third, we have developed a way to give a signal to cord blood stem cells that induces them to make large numbers of red blood cells. We are using this same method now to stimulate red blood cell production from hESC. The ultimate goals of these studies is to improve production of hematopoietic cells from hESC for use in transplantation.

Year 4

It is well recognized from adult stem cell studies that the growth of transplanted bone marrow is generated from the hematopoietic (“blood-forming”) stem and progenitor cells provided by the donor bone marrow. Mature, differentiated cells that accompany the hematopoietic stem cells, disappear rapidly after transplantation as they lack the ability to self-renew. It is thus essential when designing clinical approaches that use tissue derived from human embryonic stem cells (hESC), to specifically target the production of stem and progenitors that will survive, proliferate and differentiate normally after transplantation. We and others have shown that blood cells can be generated from hESC. However, it has become apparent more recently that the types of blood cells that hESC can produce under current conditions are more limited functionally than those found in bone marrow or cord blood. During the funding of this proposal we have compared the expression of genes in cells produced by hESC to those found in umbilical cord blood. These studies found that a gene called LNK is expressed in stem cells from hESC but not from cord blood. During completion of this grant over the past 4 months, we have found that inhibiting the expression of LNK increases the production of blood from hESC, suggesting that this pathway is a promising target for future studies aimed at increasing the production of blood-forming stem cells from hESC. Second, as part of a UCLA collaborative study we have studied six new hESC lines generated at UCLA for their ability to produce blood, blood vessels and more recently cardiac muscle. Third, we have developed a way to give a signal to cord blood stem cells that induces them to make large numbers of red blood cells. The ultimate goals of all these studies is to improve production of hematopoietic cells from hESC to provide an inexhaustible source of matched stem cells for transplantation.

© 2013 California Institute for Regenerative Medicine