Stem Cells Create a Therapeutic Niche
Published Online: May 15, 2014
Surabhi Dangi-Garimella, PhD
Stem cell therapy has gained increasing traction in various therapeutic areas, from cancer to diabetes to ocular regeneration. Although the use of embryonic stem cells is controversial, remarkable research in the field of adult induced pluripotent stem cells (iPSCs) has highlighted the tremendous potential of this unique treatment in development and regeneration. Additionally, understanding how stem cells function would improve our insight into various diseases—to fathom “what went wrong.”
Globally, patients are actively being recruited to participate in clinical trials of these regenerative therapies. A biotechnology company, Advanced Cell Technology, is testing human embryonic stem cell (hESC)-derived retinal cells for 2 different eye diseases: Stargardt’s macular dystrophy,1 which is a form of juvenile macular degeneration, and age-related macular degeneration.2 These are primarily phase 1 and 2 safety and efficacy trials, and a preliminary report published in early 2012 did not observe any safety issues with the therapy.3 Hematopoietic stem cells (HSCs), isolated from the bone marrow or umbilical cord blood, have been widely used to treat blood cancers and other blood disorders for a while now. Osiris Therapeutics, based out of Columbia, Maryland, is currently conducting phase 2 trials using human mesenchymal stem cells (MSCs) to repair heart tissue following a heart attack, repair lung tissue in chronic obstructive pulmonary disease patients, and protect pancreatic beta cells in patients with newly diagnosed type 1 diabetes mellitus.4
While bone marrow transplants for numerous blood disorders, including cancer, have been covered by insurance policies for some time now, stem cell therapies are increasingly gaining attention with improved and less ethically challenging procedures being developed from adult stem cells.
Stem cells, during early stages of development (in infants and children), have the unique potential to develop into any cell type, a property defined as “pluripotency”. Additionally, stem cells, even in adults, have “regenerative” potential, which helps them replenish damaged tissues and organs. These cells present distinct behavior depending on their site or location in the body, and they respondrespond to specific environmental cues. For example, stem cells in the gut and HSCs regularly divide to repair and replenish worn-out tissues, while stem cells in organs like the pancreas or the heart divide only under specific conditions.5
Distinct from other cell types, stem cells have the ability to undergo cell division and replicate, even after dormancy. Additionally, following specific cues, they can be prompted to differentiate into tissue- or organ-specific cells with special functions.5 Although every human organ (except nerve cells) can undergo repair by stem cells, the process dwindles with age, or is quite inactive in some organs and tissues.6 Most of the current research, independent of the therapeutic area, is geared toward understanding the stimuli that activate/reactivate stem cells to allow for age- or disease-related tissue damage.
Types of Stem Cells
The human body is primarily the source of 2 types of stem cells: embryonic stem cells and adult or somatic stem cells. hESCs are derived from embryos that remain unused following in vitro fertilization, following the informed consent of the donor.5 These cells need specific signals to differentiate to the required cell type, but they run the risk of developing into a tumor if injected directly.7 Thus, in addition to the associated ethical issues, tumor formation and transplant rejection are some of the barriers faced with hESCs.8
The use of adult stem cells, such as HSCs, does not involve any ethical issues, and when obtained from the recipient, the cells are not susceptible to immune rejection. An adult stem cell—an undifferentiated cell that exists among differentiated cells in a tissue or organ—is capable of generating the cell types of the tissue in which it resides, and maybe unipotent or multipotent. The field is burgeoning, and there is tremendous excitement among researchers to use adult stem cells in therapy. While HSCs have long been used in stem cell transplants, MSCs (non-HSCs) can generate cartilage, bone, and fat cells to form blood and fibrous connective tissue (Figure 1).5
Exciting, albeit controversial, results of human cloning were recently published in the journal Cell Stem Cell following collaborative research conducted by scientists at the CHA Stem Cell Institute in Seoul, Korea, the Research Institute for Stem Cell Research (a part of the CHA Health Systems), and the company Advanced Cell Technology. The scientists “reprogrammed” an egg cell by removing its DNA and replacing it with nuclei from 2 adult donors aged 35 years and 75 years. The experimental procedures could successfully generate 2 karyotypically normal diploid ESC lines. This technique had previously been developed, but with infant/fetal donor cells, which, unlike adult cells, are not associated with agerelated changes such as shortened telomerases and oxidative DNA damage.9
Extracting and then maintaining adult stem cells in the laboratory is extremely difficult, as they have a limited capacity to divide in culture.5 The discovery of the “transdifferentiation” process of adult stem cells, wherein adult stem cells are subjected to certain differentiation techniques to generate cell types different from the predicted types, was therefore very exciting.8 Taking the process a step further, researchers in Japan developed a technique to reprogram normal adult cells into stem cells, called induced pluripotent stem cells (iPSCs), by the forced introduction of a set of transcription factors into the cells.10 These transcription factors (different combinations of Oct4, Sox2, Klf4, c-Myc, Nanog, Lin28) regulate important steps in early embryonic development and force the adult somatic cells into an embryonic stem cell–like state. This technique has essentially revolutionized the field of regenerative medicine; the patient himself could now be an unlimited source of immune-matched pluripotent cells.11
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