page_title: Induced stem cells
section_title: Rejuvenation to iPSCs
hierarchical_section_title: Induced stem cells / Rejuvenation to iPSCs
caption_attribution_description: English: Overview of iPS cells
context_page_description: Induced stem cells are stem cells derived from somatic, reproductive, pluripotent or other cell types by deliberate epigenetic reprogramming. They are classified as either totipotent, pluripotent or progenitor or unipotent – according to their developmental potential and degree of dedifferentiation. Progenitors are obtained by so-called direct reprogramming or directed differentiation and are also called induced somatic stem cells.
  Three techniques are widely recognized:
  Transplantation of nuclei taken from somatic cells into an oocyte lacking its own nucleus
  Fusion of somatic cells with pluripotent stem cells and
  Transformation of somatic cells into stem cells, using the genetic material encoding reprogramming protein factors, recombinant proteins; microRNA, a synthetic, self-replicating polycistronic RNA and low-molecular weight biologically active substances.
context_section_description: iPSc were first obtained in the form of transplantable teratocarcinoma induced by grafts taken from mouse embryos. Teratocarcinoma formed from somatic cells. Genetically mosaic mice were obtained from malignant teratocarcinoma cells, confirming the cells' pluripotency. It turned out that teratocarcinoma cells are able to maintain a culture of pluripotent embryonic stem cell in an undifferentiated state, by supplying the culture medium with various factors. In the 1980s, it became clear that transplanting pluripotent/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. However, putting teratocarcinoma cells into the embryo at the blastocyst stage, caused them to become incorporated in the inner cell mass and often produced a normal chimeric (i.e. composed of cells from different organisms) animal. This indicated that the cause of the teratoma is a dissonance - mutual miscommunication between young donor cells and surrounding adult cells (the recipient's so-called "niche").
  In August 2006, Japanese researchers circumvented the need for an oocyte, as in SCNT. By reprograming mouse embryonic fibroblasts into pluripotent stem cells via the ectopic expression of four transcription factors, namely Oct4, Sox2, Klf4 and c-Myc, they proved that the overexpression of a small number of factors can push the cell to transition to a new stable state that is associated with changes in the activity of thousands of genes.
  Reprogramming mechanisms are thus linked, rather than independent and are centered on a small number of genes.
  IPSC properties are very similar to ESCs. iPSCs have been shown to support the development of all-iPSC mice using a tetraploid (4n) embryo, the most stringent assay for developmental potential. However, some genetically normal iPSCs failed to produce all-iPSC mice because of aberrant epigenetic silencing of the imprinted Dlk1-Dio3 gene cluster.  A team headed by Hans Schöler (who discovered the Oct4 gene back in 1989) showed that Oct4 overexpression drives massive off-target gene activation during reprogramming deteriorating the quality of iPSCs. Comparing to OSKM (Oct4, Sox2, Klf4 and c-Myc)that show abnormal imprinting and differentiation patterns, SKM (Sox2, Klf4 and c-Myc) reprogramming generates iPSCs with high developmental potential (nearly 20-fold higher than that of OSKM) equivalent to embryonic stem cell, as determined by their ability to generate all-iPSC mice through tetraploid embryo complementation
  An important advantage of iPSC over ESC is that they can be derived from adult cells, rather than from embryos. Therefore, it became possible to obtain iPSC from adult and even elderly patients.
  Reprogramming somatic cells to iPSC leads to rejuvenation. It was found that reprogramming leads to telomere lengthening and subsequent shortening after their differentiation back into fibroblast-like derivatives. Thus, reprogramming leads to the restoration of embryonic telomere length, and hence increases the potential number of cell divisions otherwise limited by the Hayflick limit.
  However, because of the dissonance between rejuvenated cells and the surrounding niche of the recipient's older cells, the injection of his own iPSC usually leads to an immune response, which can be used for medical purposes, or the formation of tumors such as teratoma. The reason has been hypothesized to be that some cells differentiated from ESC and iPSC in vivo continue to synthesize embryonic protein isoforms. So, the immune system might detect and attack cells that are not cooperating properly.
  A small molecule called MitoBloCK-6 can force the pluripotent stem cells to die by triggering apoptosis (via cytochrome c release across the mitochondrial outer membrane) in human pluripotent stem cells, but not in differentiated cells. Shortly after differentiation, daughter cells became resistant to death. When MitoBloCK-6 was introduced to differentiated cell lines, the cells remained healthy. The key to their survival, was hypoth
caption: Human somatic cells are made pluripotent by transducing them with factors that induces pluripotency (OCT 3/4, SOX2, Klf4, c-Myc, NANOG and LIN28). This results in the production of IPS cells, which can differentiate into any cells of the three embryonic germ layers (Mesoderm, Endoderm, Ectoderm).
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