Embryos contain embryonic stem (ES) cells, undifferentiated cells that will form all cell types within the body. Stem cells in the adult are referred to as adult stem cells or somatic stem cells and in contrast to embryonic stem cells, these can form only a few different cell types. Induced pluripotent stem cells (iPS cells) are generated in the laboratory. They are derived from adult cells which are treated with factors that reprogram the cell back to an undifferentiated state.
Stem cells are able to divide many times, renewing themselves over long periods, while remaining unspecialized . After each cell division a stem cell chooses to either remain a stem cell or start to become a specialized cell type like blood, muscle or skin. Adult stem cells repair or maintain the tissues in which they reside. The stem cell niche is the physical and biochemical environment where stem cells reside within the tissue .
Research into stem cell niches and signals that cue stem cells to differentiate into different cell types guides regenerative medicine and tissue engineering strategies . Regenerative medicine aims to regrow, repair or replace damaged or diseased tissues by modulating the function of endogenous stem cells in the body, introducing stem cells as therapies or by engineering tissues and organs . Organoids are mini versions of organs such as brain, intestines and retinas, created by growing 3D cell cultures from stem cells . Outside of medicine, stem cell knowledge and tissue engineering strategies are being applied to culturing animal products like meat and leather without animals .
Embryonic Stem Cells
For mammals, after fertilization and for the first few cell divisions, the cells of an embryo are totipotent, meaning they can produce all cell types . Several days after fertilization, at the blastocyst stage, an area called the inner cell mass (ICM) contains cells that will form all the cells in the body. Cells from the ICM, when cultured are embryonic stem (ES) cells . They are pluripotent and can form all cells of the body but not the extraembryonic tissues like placenta . Embryonic stem cells were isolated and grown in the laboratory from mouse embryos in 1981, and from human embryos in 1998 . The human embryos used to generate human embryonic cell lines were left over from in vitro fertilization procedures and donated for research with informed consent .
Taking ES cells and differentiating them into different cell types in culture gives scientists insights into human development and the genes, gene products and physical cues that control the process that an embryo goes through as it develops into an adult . Defects in these cues or the cell response to these cues underlie many birth defects and diseases including cancer .
Induced Pluripotent Stem Cells
Cloning of Dolly the sheep in 1996 involved removing the nucleus from an egg and replacing it with the nucleus of an adult mammary gland cell . Factors in the egg environment reprogrammed epigenetic marks which dictate cell-specific gene expression in the mammary gland nucleus, erasing cell specialization so that it regained the ability to form all tissues in the body . This propelled researchers like Shinya Yamanaka and Kazutoshi Takahashi of Kyoto University, Japan, to find out which factors were capable of reprogramming adult cells into pluripotent stem cells. In 2006, Yamanaka and Takahashi narrowed down the factors to four, Oct3/4, Sox2, c-Myc and Klf4, which are sufficient to reprogram mouse skin cells into cells similar to ES cell which are called induced pluripotent stem (iPS) cells . Human iPS cells were generated in 2007 by Yamanaka’s group in collaboration with Kiichiro Tomoda at Gladstone Institute of Cardiovascular Disease, San Francisco .
In 2007 Rudolf Jaenisch and Tim Townes of the Whitehead Institute for Biomedical Research, Cambridge and University of Alabama respectively, demonstrated that skin cells (fibroblasts) harvested from the tail tip of mice modelling sickle cell anemia could be reprogrammed into iPS cells, the mutation corrected, and the corrected iPS cells differentiated into blood progenitor cells . These blood progenitor cells, partway between stem cells and fully differentiated blood cells could be transplanted back into the mice to rescue their deficiency . In 2013 Takahashi’s team generated iPS cells from skin fibroblast cells of patients suffering from the eye condition age-related macular degeneration, which leads to blindness . From these iPS cells they created sheets of specialized eye tissue called retinal pigment epithelium (RPE) which was implanted into a patient, stopping disease progression and improving her vision.
Viruses are used to introduce the genes of cell reprogramming factors so they can be expressed in adult cells . The process, which can cause cancer in mice, is being tested for safety before using this technique in humans . Non-viral delivery strategies such as transient delivery of DNA, RNA and proteins are being investigated . Due to the high cost of developing and testing therapies, donor-derived iPS cell banks may be more feasible than making them from individual patients .
Aside from therapeutic possibilities, iPS cells are used to obtain unlimited supplies of patient cells to model their diseases in tissue culture both to understand the disease and test drug treatments . Researchers use CRISPR-Cas9 gene editing to make disease-associated mutations to their iPS cell lines and compare these to the non-edited versions . Neuroscientist Guo-li Ming at Johns Hopkins University is using iPS cells to generate brain organoids to study how Zika virus infections in pregnant women lead to microcephaly .
Adult Stem Cells
The idea of stem cells, self-renewing cells that could specialize into different cell types was eluded to by the turn of the 20th century and was first demonstrated in blood . Hematopoietic (blood-forming) cell research grew from the understanding that Hiroshima and Nagasaki victims of atomic bombs who were subjected to low does of irradiation died of hematopoietic failure and an interest in protecting military personnel from irradiation from nuclear weapons, and . The existence of stem cells was demonstrated in the characterization of hematopoietic stem cells (HSCs, blood-forming stem cells) by Ernest McCulloch and James Till in the 1960s at University of Toronto, Canada . In understanding how bone marrow transplants save mice from irradiation, McCulloch and Till along with fellow University of Toronto researcher, Lou Siminovitch showed that these bone marrow derived cells were blood stem cells that self-renewed and differentiated into specialized blood cell types .
Besides bone marrow, adult stem cells have been identified in brain, peripheral blood blood vessels, skeletal muscle, teeth, heart, gut, liver, ovarian epithelium and testis . In their stem cell niche, they may remain in a quiescent state until they are activated when needed to maintain or repair tissues .
Stem Cell Therapies
Hematopoietic stem cells have been used regularly since the 1960s in the form of bone marrow transplants to replenish bone marrow after chemotherapy and radiotherapy treatments that destroy resident blood forming cells . Blood stem cells in peripheral blood and umbilical cord blood can also be used in blood cell replenishing treatments .
Mesenchymal stromal cells (MSCs), also called mesenchymal stem cells, are found in circulation and have been shown to migrate to sights of injury . MSCs, which have also been isolated from bone marrow, adipose and umbilical cord blood. MSCs can differentiate into bone precursors (osteoblasts), fat cells (adipocytes), cartilage cells (chondrocytes) and neurons . Clinical trials for MSCs in repairing bone, cartilage and blood vessel damage are underway. MSCs have immunosuppressive and anti-inflammatory properties and due to those properties are being tested in clinical trials to treat Multiple Sclerosis and sepsis .
Skin stem cells have been used since the 1980s to grow skin grafts for patients with severe burns . Limbal stem cells are adult stem cells in the eye that are used to repair the cornea .
The first lab-grown beef burger emerged in 2013 from Mosa Meat, after being cultured over a period of three months, using bovine adult stem cells from a cow muscle biopsy at a cost of $330,00 . These muscle stem cells called satellite cells are cultured into myoblasts, which multiply further before forming muscle fibers . Several hundred kg of meat could be produced from one biopsy . Since fat in meat contributes to taste and texture, the culturing of fat cells using adipose stem cells or satellite cells treated with transcription factor PPAR-gamma or PPRG are in development . Israel’s Aleph Farms is developing 3D tissue engineered meat that combines muscle fibers with blood vessels .
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