Studies of Blood Cell Formation 
David A. Williams, M.D. — Assistant Investigator 
Dr. Williams is also Associate Professor and Kipp Investigator of Pediatrics at Indiana University School of 
Medicine, Indianapolis. It was here that he received his medical degree, after graduating in biology from 
Indiana State University. His postdoctoral training includes a pediatric residency at Children's Hospital 
Medical Center, Cincinnati; research fellowships with Richard Mulligan at the Massachusetts Institute of 
Technology Center for Cancer Research and the Whitehead Institute for Biomedical Research; and clinical 
fellowships in pediatric hematology /oncology at Harvard Medical School, the Children 's Hospital, and 
'%t, Dana-Farber Cancer Institute, Boston. He was Assistant Professor of Pediatrics at Harvard Medical School 
before assuming his present position. 
THE goal of work in our laboratory is to under- 
stand the relationship between supporting 
cells in the bone marrow cavity and the develop- 
ment of blood cells. The production of blood 
cells from primitive "stem cells" in the marrow 
is dependent on interactions between the latter 
cells and certain supporting cells. Understanding 
the process of blood cell formation is important 
for treatments that utilize bone marrow trans- 
plantation, including gene transfer methods to 
correct genetic diseases affecting the blood- 
forming system. 
Studies of the Bone Marrow Environment 
The production of enormous numbers of blood 
cells in the bone marrow environment and their 
delivery to the blood circulation constitute a 
highly regulated and complex process. Either ex- 
cessive or insufficient production of the primi- 
tive stem cells or the more mature daughter cells 
is associated with human diseases. Little is 
known, however, about how this process is regu- 
lated. Our approach to the problem has been to 
simplify interactions between stem cells and sup- 
porting cells by immortalizing single supporting 
cells from the bone marrow and studying these 
interactions in detail. 
In collaboration with Vikrum Patel at North- 
western University, we have defined a protein 
and its receptor that appear to be important in 
anchoring stem cells to supporting cells. This in- 
teraction can be blocked in mice and in vitro 
using antibodies to the receptor. The stem cells 
that adhere to supporting cells (stromal cells) us- 
ing this receptor appear to have a high capacity to 
form new stem and daughter cells. The adherence 
of stem cells to supporting cells is important in 
the survival of stem cells both in vitro and in the 
bone marrow cavity. A better understanding of 
this interaction may lead to new methods for 
growing blood cells and expanding the number 
of stem cells in the laboratory. 
An important protein in the growth of blood 
cells was recently identified in our laboratory as 
"Steel factor." This protein is defective in a 
mouse mutant (Steel mouse) , which has a form of 
aplastic anemia, as well as infertility and skin ab- 
normalities. The protein is normally made in two 
forms that differ with respect to how it is pre- 
sented to blood stem cells in the bone marrow 
environment. We are investigating the role of 
these two different types of Steel factor 
presentation. 
Deniz Toksoz, a former HHMI associate, has re- 
cently shown that presentation of Steel factor in a 
localized fashion leads to survival of immature 
human blood cells (termed progenitor cells) 
longer in culture than when the presentation is 
nonlocalized. This observation, in combination 
with the identification of proteins involved in 
blood cell adhesion (described above) , may have 
important implications in developing a system 
for growing bone marrow cells in vitro. Manas 
Majumdar, an HHMI associate, is currently study- 
ing the role of this protein on blood formation 
during development of the mouse. 
Studies on the role of the supporting cells in 
the bone marrow have also led us to the identifi- 
cation and production (by recombinant meth- 
ods) of another protein involved in blood forma- 
tion, termed IL-11 (interleukin- 11 ) . In recent 
work utilizing IL-11, Xunxiang Du has demon- 
strated that it has the capacity to help bone 
marrow stem cells reestablish blood formation 
after intravenous injection (i.e., bone marrow 
transplantation) in mice. This protein affects the 
growth of several different types of blood cells, 
including platelets and neutrophils. We are in- 
vestigating the use of this growth factor to pre- 
vent some of the severe complications of chemo- 
therapy, such as infection and bleeding. This 
work is also supported by grants from the Na- 
tional Institutes of Health. 
Effects of Growth-regulating Proteins 
During Blood Development in the 
Early Embryo 
In the developing mammalian embryo, blood 
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