Induced stem cells (iSC) are stem cells artificially derived from some other (somatic, reproductive, pluripotent etc.) cell types by induced (i.e. initiated, forced) epigenetic reprogramming. In accordance to the developmental potentiality and the degree of cell dedifferentiation caused by induced reprogramming they are distinguished and subdivided as: induced totipotent, induced pluripotent stem cells (iPSc) and, obtained by so-called direct reprogramming or directed forced differentiation, induced progenitor (multipotent or unipotent) stem cells, also called induced somatic stem cells. Currently, there are three ways to reprogram somatic cells into stem cells[1] These are:

The reversible transformation of one differentiated cell type to another type of mature differentiated cells is called metaplasia.[22] This transition from one cell type to another can be a part of the normal maturation process, or caused by some of its inducing stimulus. For example: transformation of cells of the iris to the lens in the process of maturation and transformation of the retinal pigment epithelium cells into the neural retina during regeneration in adult newt eyes. This process allows the body to replace the original cells not suitable to new conditions, into new cells which are more suited to new conditions. In experiments on cells in Drosophila imaginal discs, it was found that there are a limited number of standard discrete states of differentiation and the cells have to choose one of them. The fact that transdetermination (change of the path of differentiation) often take place not in one, but in a group of cells shows that it is not caused by a mutation but is induced.[23][24]

Some types of mature, specialized adult cells can naturally revert to stem cells. For example, differentiated cells, which are called chief cells and express the stem cell marker Troy, normally produce digestive fluids for the stomach, yet they can change back into stem cells to make temporary repairs in significant stomach injuries, such as a cut or damage from infection. Moreover theyre making this transition even in the absence of noticeable injuries and are capable of replenishing entire gastric units, essentially serving as quiescent reserve stem cells.[25] Differentiated airway epithelial cells can revert into stable and functional stem cells in vivo.[26] After injury, mature terminally differentiated kidney cells dedifferentiate into more primordial versions of themselves, and then differentiate into the cell types needing replacement in the damaged tissue[27] Macrophages can self-renew by local proliferation of mature differentiated cells.[28] In Newts, muscle tissue is regenerated from specialized muscle cells that dedifferentiate and forget what type of cell they've been. This capacity to regenerate tissue does not decline with age, which may be linked to their ability to make new stem cells from muscle cells on demand.[29]

It should be noted that there are also a variety of nontumorigenic stem cells with the ability to generate the multiple cell types. For instance, multilineage-differentiating stress-enduring (Muse) cells are the stress-tolerant adult human stem cells that can self-renew; form characteristic cell clusters in suspension culture that express a set of genes associated with pluripotency; and can differentiate into endodermal, ectodermal, and mesodermal cells both in vitro and in vivo.[30][31][32][33]

Detailed description of some other well-documented examples of transdifferentiation, and their significance in development and regeneration are reviewed in.[34]

Induced totipotent cells usually can be obtained by reprogramming somatic cells by somatic-cell nuclear transfer (SCNT) to the recipient eggs or oocytes.[3][5][35][36][37] Sometimes may be used the oocytes of other species, such as sheep.[38] New possibilities for creating genetically modified animals opens method of induced androgenetic haploid embryonic stem cells, which can be used instead of sperm. These cells, synchronized in M phase and injected into the oocyte allow to get viable offspring.[39] These developments, together with data on the possibility to obtain unlimited number of oocytes from mitotically active reproductive stem cells[40] offer the possibility of industrial production of transgenic farm animals. Repeated recloning of viable mice through a somatic cell nuclear transfer method that includes a histone deacetylase inhibitor trichostatin, added to the cell culture medium,[41] show that it may be possible to reclone animals indefinitely without any visible accumulation of reprogramming or genomic errors [42] However, research into technologies to develop sperm and egg cells from stem cells bring up bioethical issues.

Such technologies may also have far-reaching clinical applications for overcoming cytoplasmic defects in human oocytes.[43][44][45] For example, the technology have been developed that could prevent inherited mitochondrial disease being passed on to the next generation. Mitochondria, often described as the powerhouse of the cell, contain genetic material, which is passed from mother to child. Mutations on mitochondrial DNA can cause diabetes, deafness, eye disorders, gastrointestinal disorders, heart disease, dementia and several other neurological diseases. The nucleus from one human egg cell have been transferred to another egg, effectively swapping the cell cytoplasm, which includes the mitochondria (and their DNA), creating a cell that could be regarded as having two mothers. The eggs were then fertilised, and the resulting embryonic stem cells carried the swapped mitochondrial DNA.[46]

Read more about the latest achievements of the cloning techniques and the generation of totipotent cells, in:[47]

See also main article: induced pluripotent stem cells (iPSc)

First iPSc were obtained in the form of transplantable teratocarcinoma induced by the graft taken from mouse embryos.[48] It was shown that teratocarcinoma formed from somatic cells.[49] The fact that normal genetically mosaic mice can be obtained from malignant teratocarcinoma cells confirmed their pluripotency.[50][51][52] It turned out that teratocarcinoma cells are able to maintain a culture of pluripotent embryonic stem cells in an undifferentiated state, by supplying the culture medium with various factors.[53] Thus, as early as in the 1980s, it became clear that the transplantation of pluripotent or embryonic stem cells into the body of adult mammals, usually leads to the formation of teratomas, which can then turn into a malignant tumor teratocarcinoma.[54] If, however, to put the teratocarcinoma cells into the early mammal embryo (at the blastocyst stage), they became incorporated in the cell mass of blastocysts and from such a chimeric (i.e. composed of cells from different organisms) blastocyst often develops normal chimeric animal.[55][56][57] This indicated that the cause of the teratoma is a dissonance - mutual misunderstanding of "speech" of young donor cells and surrounding adult cells (so-called niche) of the recipient.

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