Human bone marrow cells (left) were coaxed to become pluripotent, all-purpose stem cells (right) in a new study by a team led by University of Wisconsin-Madison stem cell researcher Igor Slukvin, a professor of pathology and laboratory medicine in the UW School of Medicine and Public Health. Slukvin’s group turned banked healthy and diseased human bone marrow into blank-slate stem cells, which have potential use in therapy and could become a powerful laboratory model, as the new induced cells made from diseased marrow carry the same genetic mutations that cause the blood cancer chronic myeloid leukemia. Photo: Jeff Miller |
By coaxing
healthy and diseased human bone marrow to become embryonic-like stem cells, a
team of Wisconsin scientists has laid the
groundwork for observing the onset of the blood cancer leukemia in the
laboratory dish.
“This is
the first successful reprogramming of blood cells obtained from a patient with
leukemia,” says Univ. of Wisconsin-Madison stem cell researcher Igor
Slukvin, who directed a study aimed at generating all-purpose
stem cells from bone marrow and umbilical cord blood. “We were able to
turn the diseased cells back into pluripotent stem cells. This is important
because it provides a new model for the study of cancer cells.”
The research was
reported today in the journal Blood by Slukvin and colleagues from the WiCell
Research Institute and the Morgridge Institute for
Research, private research centers in Madison.
Slukvin’s group,
using banked healthy and diseased bone marrow and cord blood, employed a
technique developed in 2009 by Wisconsin stem
cell pioneer James Thomson that sidesteps the problems posed by the genes and
viral vectors used to induce mature cells to regress to a stem cell state.
According to the
new study, which was funded by the National Institutes of Health and The
Charlotte Geyer Foundation, reprogramming blood cells to become induced stem
cells is many times more efficient than the reprogramming of skin cells, which
were the first mature cells to be guided back to an embryonic stem cell-like
state.
The new work
could open to science vast repositories of banked tissue, both healthy and
diseased, such as bone marrow, the soft tissue in bones that helps make blood,
and umbilical cord blood. The work could underpin insightful models capable of
unmasking the cellular events that go awry and cause cancers such as leukemia,
and could aid the development of new stem cell-based therapies, according to
Slukvin.
Of particular
note in the new study, says Slukvin, is the reprogramming of marrow cells from
a patient with chronic myeloid leukemia, a cancer of the blood that kills about
1500 people a year in the United
States. The disease, like all leukemias,
starts in the cells that produce white blood cells in bone marrow.
According to
Slukvin, the induced stem cells generated from the diseased tissue retain the
exact same complex of genetic abnormalities found in the mature cancer cells.
That means that when the induced cells are turned back into blood, scientists
could, in theory, watch cancer develop from scratch as cells bearing cancer
mutations become cancer stem cells.
“When we
differentiate induced stem cells back to blood, we can identify the stages when
the abnormality that leads to cancer manifests itself,” Slukvin explains.
The ability to
pinpoint the very earliest stages of cancer is a major focus of biomedical
science.
“This is
very important for developing new leukemia drugs,” says Slukvin. “A
major focus of leukemia research is to find ways to try and eliminate the most
immature leukemia cells—cancer stem cells.”
The work by
Slukvin and his team may represent the first step in a new understanding of the
cascade of events that results in blood diseases such as leukemia.
Employing the
reprogramming technique developed by Thomson and his colleagues, Slukvin
emphasizes, is important because it eliminates the exotic reprogramming genes,
some of which are cancer-related genes, from the induced stem cell equation. In
the case of chronic myeloid leukemia and other blood diseases, obtaining stem
cells that do not have the genetic reprogramming factors is very important.
“When you
use viruses (to ferry genes into a cell) you have chromosomal
integration,” the Wisconsin researcher
notes. “Some of the reprogramming factors are oncogenes and would
interfere with a study of chronic myeloid leukemia” whose abnormalities
are also encoded on the chromosome.
In addition to
Slukvin, an investigator at the Wisconsin National Primate Research Center
(WNPRC) and an associate professor of pathology at the UW School of Medicine and
Public Health, authors of the new study include Kejin Hu, Junying Yu and
Kyung-Dal Choi of the WNPRC; Kran Suknuntha of the UW School of Medicine and
Public Health; Shulan Tian, Ron Stewart and James A. Thomson of the Morgridge
Institute for Research; and Karen Montgomery of the WiCell Research Institute.
