Conversion of Dermal to Hematopoietic Cells Through Genetic Manipulation
Importance of the Pluripotent Cell Stage
During the pluripotent stage, a cell can differentiate into any of the three major tissue types: endoderm, mesoderm, or ectoderm. A pluripotent cell can develop into a fetal or an adult cell type. Due to the cell's inherent potential to become one of several types of cells, pluripotent cells are one of the focal points of research currently being conducted in the United States and elsewhere. Several studies have derived an 'induced' pluripotent stem (iPS) cell from a non-pluripotent cells, such as an adult somatic cell, by inducing a specific gene expression . However, a notable study has demonstrated for the first time that it is possible to bypass the pluripotent stage while converting skin cells into blood cells .
Bypassing the Pluripotent Stage
In a groundbreaking study published in the science journal Nature in November 2010, Eva Szabo, Ph.D., Mickie Bhatia, Ph.D., and a team of other scientists at McMaster University in Hamilton, Ontario in Canada demonstrated the ability to generate hematopoietic progenitors and mature cells, also known as blood cells, directly from dermal, or skin, fibroblasts by bypassing the pluripotent stage (see Figure 1). Since the pluripotent stage causes cells to differentiate into one of many cell types, bypassing this stage allows red blood cells to be directly produced. The study showed that expression of the OCT4 activated blood cell transcription factors, in combination with particular cytokine treatment, can in fact lead to the production of cells that express the pan-leukocyte marker CD45 , which has been identified as a white blood cell common antigen [2, 3]. During the two year study funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Stem Cell Network and the Ontario Ministry of Research and Innovation, researchers discovered that by adding the OCT4 gene and a group of proteins commonly referred to as blood transcription factors to skin cell samples, various types of blood cells including red blood cells (RBC's), white blood cells (WBC's), and platelets can be made from skin cells [2, 4].
a. SubtleGuest/Wikimedia Commons. b. A.D.A.M., Inc.
A technique called "direct reprogramming," which involves gene insertion by a virus vector and exposure to numerous regulatory proteins, was the main method used in this study. Both adult dermal cells and neonatal foreskin cells were used in order to ensure that the transformation from skin cell to blood cell is not limited by age and cell maturity. At this point a virus was used to transfect the skin cells with the homeodomain OCT 4 gene, which encodes for a transcription factor; a homeodomain is a DNA sequence found within genes that are involved in the regulation of patterns of anatomical development [2, 4]. The transcription factor then is involved in activating other genes and thus triggering production of other proteins . The cells were then exposed to cytokines, which are immune-stimulating proteins. As a result of the OCT4 gene transfection and cytokine exposure, the epithelial cells changed into various blood cell types (RBC's, WBC's, and platelets) that expressed the CD45 antigen. These blood cells showed a capacity to not only proliferate and form colonies (in vitro) but also to attach and grow in mice, a process known as engraftment (in vivo) .
Before this particular study, scientists had previously converted skin cells into pluripotent stem cells that could differentiate into any cell type. The research done by Bhatia and his team of researchers is the first study to show that it is possible to bypass this pluripotent stage and to produce adult blood cells, rather than embryonic stem cells. This direct conversion is a beneficial technique because of its greater efficiency and feasibility. It should be noted that since this technique involves no embryonic stem cells, the highly political climate surrounding stem cell research can be bypassed as well, and the moral, ethical, and legal concerns that have come to significant light in recent years do not become entangled with this study . Other researchers have followed in Bhatia's footsteps and confirmed the ability to bypass the pluripotent stage in cell conversion. For example, a study led by Dr. Hans Schöler at the Max Planck Institute for Molecular Biomedicine in Germany demonstrated that through use of specific transcription factors and without utilizing the pluripotent stage, skin cells (known as fibroblasts) from mice can be induced into forming induced neural stem cells (iNSCs) .
Szabo and Bhatia's findings have the potential to be tremendously influential. A direct conversion from skin cells to blood cells can be used for individuals preparing to undergo surgery, those who are diagnosed with cancer, and individuals who suffer from specific blood disorders like anemia [7, 8]. Bhatia, who is also the scientific director at the university's Stem Cell and Cancer Research Institute, noted that patients with anemia can be treated on a case by case basis, meaning that if the patient requires only red blood cells, then a cocktail of only red blood cells can be produced from the skin cells by following the corresponding "recipe." Furthermore, if a patient has a blood clotting disorder, then platelets can be produced and administered [8-10]. Using this procedure of direct cell conversion, scientists can create and use the patient's own derived blood cells to provide necessary transfusions. Furthermore, this advancement can be used to supply those who have lost the ability to produce their own cells due to chemotherapy or leukemia with genetically identical replacement cells [7-10].
In this light, this discovery may have great impact on research in oncology and other related diseases. One of the many detrimental side effects of chemotherapy is the slowed production of blood cells; since chemotherapy does not differentiate between cancer cells and fast-growing healthy cells, such as RBC's, chemotherapy can stunt the growth and division of RBC's. Consequently, patients are often given breaks in chemotherapy in order to recover their blood count, thereby providing the cancer cells more time to proliferate. Bypassing the pluripotent stage to produce RBC's may provide patients with a steady blood count, allowing them to continue chemotherapy in a timely manner. Similarly, this procedure may benefit patients diagnosed with leukemia by supplying them with blood cells made from their own skin, thereby providing the ultimate perfect biological match .
In addition to its uses in cancer, this direct conversion method can be used to generate transplant tissue. Moreover, this research could reduce the costs of producing synthetic blood, which is an expensive experimental method. Furthermore, this procedure may benefit patients in need of bone marrow transplants by bypassing the problem of finding exact matches in order to avoid an immune response by the recipient's body [2, 3, 11]. Schöler's findings regarding bypassing the pluripotent stage to produce neural stem cells can be used to harvest neurons from skin cells, creating the possibility of treating brain damage .
The team of researchers responsible for this incredible advancement is now working to make large quantities of blood by growing skin cells in a lab before converting them into blood cells [8, 11, 12]. Eventually, scientists are planning on freezing and thawing the blood cells in order to determine how well they can withstand different conditions. There is also hope that other cells can one day also be produced from skin cells [8, 10-12]. The team definitely does not plan on stopping at their achievements thus far. They are confident that significant improvements can still be made in terms of number of cells transformed and the efficiency of the process. Bhatia plans to begin clinical trials in 2012 [2, 7, 11, 12].
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