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Induced Pluripotent Cells Created From Blood

American Society of Hematology, March 30, 2009

In the past, iPS (induced pluripotent stem) cells were obtained by reprogramming dermal fibroblasts obtained by skin biopsy, first in mice and later in humans. The reprogramming involved a de-differentiation process by which ordinary somatic (non-stem cell) cells were induced to revert to a more primitive state in which they exhibit a pluripotency that resembles that of embryonic stem cells. Now, for the first time, scientists have derived iPS cells from reprogrammed CD34+ cells that are mobilized from human peripheral blood.

In a study led by Dr. Yuin-Han Loh of Children's Hospital in Boston, and in collaboration with scientists at the Dana-Farber Cancer Institute, the Brigham and Women's Hospital, the Howard Hughes Medical Institute and the Harvard Stem Cell Institute, researchers have developed a new application of the same laboratory methods that are by now well known among stem cell scientists for deriving iPS cells. Using retroviral transduction of Oct4/SOX2/KLF4 (transcription factors involved in cellular self-renewal and differentiation) and c-Myc (a gene involved in protein-coding, a mutated version of which is known to be oncogenic, or in other words, it can cause cancer; in fact the entire Myc family of genes are known as proto-oncogenes and are implicated in some types of cancer when mutated or overexpressed), the researchers succeeded in generating a blood-derived iPS cell which they describe as being "indistinguishable from human embryonic stem cells (hESCs) with respect to morphology, expression of surface antigens and pluripotency-associated transcription factors", among other characteristics. In fact, the newly formed iPS cells were also found to resemble hESCs in DNA methylation status at pluripotent cell-specific genes, and also, the authors point out, in the capacity of these newly formed iPS cells "to differentiate in vitro and in teratomas".

Indeed, as with hESCs and all other types of pluripotent cells, any and every type of iPS cell must be able to form teratomas (a specific type of tumor which contains cells from all 3 germ layers) since this is part of the formal scientific definition of pluripotency, and if a cell cannot form the type of tumor known as a teratoma then it is not pluripotent. By contrast, since adult stem cells are multipotent at best, not pluripotent, adult stem cells do not carry the risk of teratoma formation. CD34+ cells are already recognized as a type of "adult" stem cell and as such they do not exhibit pluripotency and therefore cannot form teratomas. This most recent study by Dr. Loh and his colleagues, however, has shown that any type of cell will be able to form dangerous teratomas once it has been reprogrammed to a more primitive, pluripotent state.

Although the lack of pluripotency was previously seen as a disadvantage of adult stem cells, increasingly it is recognized as a distinct advantage since it allows for more certainty and control of the differentiation of the adult stem cells into only the desired type of tissue, without the danger of tumor formation which is so characteristic of embryonic and fetal stem cells, and even without the simpler danger of the wrong type of tissue formation (such as the accidental formation of bone within cardiac or neurological tissue, etc.). Nevertheless, the lure of pluripotency remains irresistible to many scientists, and iPS cells are still highly coveted, especially since they can be created without having to destroy an embryo, even though iPS cells resemble embryonic stem cells in their pluripotency, which thereby circumvents the ethical debates that are inextricably entangled in embryonic stem cell research. However, as pluripotent cells, iPS cells still pose the same medical risks as do embryonic stem cells, only one of which is the danger of teratoma formation, and for this reason scientists agree that at least another decade is needed before iPS cells can become available as clinical therapies at your local neighborhood doctor's office. Meanwhile, adult stem cells are already being used in clinics around the world as therapies for a wide variety of illnesses and injuries, since, as already explained, adult stem cells are multipotent, not pluripotent, and as such they cannot form teratomas nor do adult stem cells carry any of the other medical risks that are associated with embryonic and iPS cells (such as genetic mutation and biological contamination in the case of embryonic stem cells, and cellular reprogramming agents that include cancer-causing genes delivered by dangerous retroviruses in the case of iPS cells, among other problems). In their natural state, CD34+ cells are already being used in clinics around the world to treat a wide variety of illnesses and injuries; in their reprogrammed, artificially induced pluripotent state, however, they behave just like embryonic stem cells and hence are unusable as a clinical therapy, at least until scientists figure out how to eliminate the associated dangers such as teratoma formation, among others, which even the most ambitious of stem cell scientists concedes will require another decade of research.

As one of the many "cluster of differentiation" (CD) molecules, CD34 is a glycoprotein present on the surface of some cells within the human body, and it is merely one of the many CD cell surface markers that have been identified. Cells expressing the CD34 molecule (CD34+ cells, according to the nomenclature) have been found in a number of regions throughout the human body including the dermis, but are most abundant in bone marrow and umbilical cord blood where the CD34+ cells exhibit strong hematopoietic (blood-forming) capabilities. Perhaps most importantly, CD34+ cells are also present in peripheral blood as endothelial progenitor cells (cells originating in the bone marrow that circulate throughout the blood and are capable of differentiating into the cells that line blood vessels), and in this capacity they have been found to play a central role in cardiovascular health, especially in recovery following myocardial infarction. It is believed that any event which causes acute damage to blood vessels such as a myocardial infarction will trigger the automatic mobilization of endothelial progenitor cells and their migration out of the bone marrow into the blood stream where they can repair damaged blood vessels. Heart attack patients who have been found to have high levels of circulating endothelial progenitor cells in their blood stream exhibit greater and faster improvement than do patients with lower levels of the cells circulating in their bloodstream, and a number of studies have proposed the dedicated use of concentrated amounts of endothelial progenitor cells in a variety of cardiovascular therapies. Most notably, surgeons at Harvard Medical School described in a 2007 report a method of using the cells to construct organic pediatric heart valves that would, unlike other heart valves, be capable of growing with the child.

In fact, CD34+ cells have already proven to be so useful as a type of "adult" stem cell, that one wonders why anyone would want to tamper with them and try to change anything about the characteristics of these extremely versatile cells. In their natural state, not only are CD34+ cells highly regenerative but they have also been shown to be safe, from numerous clinical therapies that have been conducted over many years around the world and reported in the medical literature. Nevertheless, when reprogrammed to a more primitive, pluripotent state, even CD34+ cells will form teratomas, just as embryonic and all other iPS cells must, by definition, do. One also wonders why Dr. Loh and his colleagues didn't try to derive iPS cells from a more ordinary type of blood cell, such as from a white blood cell (leukocyte), for example, which is also known to differentiate from hematopoietic cells within the bone marrow but which is much more plentiful within the blood than are CD34+ cells.

Since the derivation of peripheral blood involves a much easier and less invasive procedure than does the harvesting of a skin cell, proponents of iPS cells point out that the generation of iPS cells from reprogrammed human blood cells may now expedite research into patient-specific stem cells - even though patient-specific stem cell research is already being conducted with adult stem cells. Be that as it may, and even though many scientific hurdles still remain to be overcome before such iPS cells may be available as clinical therapies, nevertheless this is merely one more demonstration of the fact that pluripotent cells may be obtained through a variety of methods, without the need for embryos.

One can only wonder how much longer it will be before iPS cells will be derivable from any type of ordinary somatic cell that is obtainable from any type of tissue from anywhere throughout the adult human body.



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