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induced pluripotent stem cell (iPS)

Cells, similar to embryonic stem cells, derived from differentiated skin cells (keratinocytes), 1st in mice, then in humans Clinical significance: - used to treat sickle cell anemia in mice - induced from fibroblasts obtained from a patient with ALS [4] - induced from fibroblasts obtained from a child with childhood spinal muscular atrophy/SMN deletions & transformed into motor neurons [5] - fibroblasts from patients with Alzheimer's disease (AD), familial AD & sporadic AD induced to form iPS, then processed into neurons; differences in Abeta40 secretion, GSK3B, phospho-tau noted (see molecular pathology of AD) [9] Complications: - technique that requires introduction of genes into adult cells can induce tumors if they insert into the wrong place - transfection with mRNA rather than DNA may minimize risk of inducing tumors [5] - iPS cells often contain genetic modifications (e.g., point mutations, copy number variations) & epigenetic modifications that could render iPS cells cancerous or cause them to self-destruct after continued division [6] - screening protocols may be necessary [6] - more immunogenic & more likely than embryonic stem cells to induce rejection [7] Procedure: - 4 transcription factors (Yamanaka factors) induce fibroblasts to form induced-pluripotent stem cells in mice: - Oct4, Sox2, Klf4, cMyc - using RNA rather than DNA for transfection improves efficiency & minimizes risk of tumors Comparative biology: - induced pluripotent stem cell-derived dopaminergic progenitors functioned as midbrain dopaminergic neurons in Macaca fascicularis treated with the neurotoxin MPTP - the mature dopaminergic neurons extended dense neurites into the striatum - an increase in spontaneous movement of the monkeys after transplantation observed - no neoplasms noted within 2 years Notes: - fibroblasts may be converted directly into neurons without 1st creating induced pleuripotent stem cells [8] - depleting Mbd3 allows nearly 100% of cells to be transformed into pluripotent stem cells [10] - brief exposure of differentiated adult mouse cells to an acidic environment transforms them into the equivalent of induced pluripotent stem cells - the cells are called STAP cells - STAP cells reproduce themselves indefinitely & can be transformed into any differentiated cell type [11] - inability of others to reproduce results [11] - claims of misconduct [11] - initial reports on STAP cells retracted [11]

Related

embryonic stem (ES) cell

General

multipotent adult progenitor cell (MAPC) pluripotential stem cell

References

  1. Takahashi K et al, Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007, Nov 20, 131:861 PMID: 18035408 http://dximages.cell.com/images/images/cell/ieps/3661.pdf Yu J et al, Induced pluripotent stem cells derived from human somatic cells. Science 2007, Nov 20 PMID: 18029452 http://dx.doi.org/10.1126/science.1151526
  2. Hanna J et al, Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 2007, Dec 6 PMID: 18063756 http://dx.doi.org/10.1126/science.1152092
  3. Wernig M et al, Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. Proc Natl Acad Sci USA 2008, 105:5856 PMID: 18391196
  4. Dimos JT et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 2008 Jul 31; [e-pub ahead of print] PMID: 18669821 http://dx.doi.org/10.1126/science.1158799 - Park I-H et al. Disease-specific induced pluripotent stem cells. Cell 2008 Aug 7; [e-pub ahead of print] PMID: 18691744 http://dx.doi.org/10.1016/j.cell.2008.07.041
  5. Warren L et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 2010 Sep 30 PMID: 20888316 Journal Watch, Massachessetts Medical Society, Nov 3, 2010 http://www.jwatch.org
  6. Hussein SM et al. Copy number variation and selection during reprogramming to pluripotency. Nature 2011 Mar 3; 471:58. PMID: 21368824 - Gore A et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 2011 Mar 3; 471:63. PMID: 21368825 - Lister R et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 2011 Mar 3; 471:68. PMID: 21289626 - Pera MF. Stem cells: The dark side of induced pluripotency. Nature 2011 Mar 3; 471:46 PMID: 21368819
  7. Zhao T et al. Immunogenicity of induced pluripotent stem cells. Nature 2011 May 13; 474:212. PMID: 21572395 - Mummery C. Induced pluripotent stem cells - A cautionary note. N Engl J Med 2011 Jun 2; 364:2160. PMID: 21631331
  8. Pang ZP et al. Induction of human neuronal cells by defined transcription factors. Nature 2011 Aug 11; 476:220 PMID: 21617644 - Caiazzo M et al. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 2011 Aug 11; 476:224. PMID: 21725324 - Yoo AS et al. MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 2011 Aug 11; 476:228 PMID: 21753754 - Sendtner M. Bespoke cells for the human brain. Nature 2011 Aug 11; 476:158 PMID: 21833079
  9. Israel MA et al. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature 2012 Jan 25; PMID: 22278060
  10. Rais Y et al. Deterministic direct reprogramming of somatic cells to pluripotency. Nature 2013 Oct 3; 502:65. PMID: 24048479 http://www.nature.com/nature/journal/v502/n7469/full/nature12587.html - Loh KM and Lim B.Stem cells: Close encounters with full potential. Nature 2013 Oct 3; 502:41 PMID: 24048472 http://www.nature.com/nature/journal/v502/n7469/full/nature12561.html
  11. Obokata H et al. Stimulus-triggered fate conversion of somatic cells into pluripotency. Nature 2014 Jan 30; 505:641 PMID: 24476887 - Obokata H et al. Bidirectional developmental potential in reprogrammed cells with acquired pluripotency. Nature 2014 Jan 30; 505:676 PMID: 24476891 - Cyranoski D Mismatch alleged in acid-bath stem-cell experiment. Cell lines linked to blockbuster papers came from different mouse strain to that claimed, study suggests. Nature. March 27, 2014 http://www.nature.com/news/mismatch-alleged-in-acid-bath-stem-cell-experiment-1.14946 - Nature editorial STAP retracted. Two retractions highlight long-standing issues of trust and sloppiness that must be addressed. Nature, July 2, 2014 http://www.nature.com/news/stap-retracted-1.15488
  12. Kikuchi T, Morizane A, Doi D et al. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model. Nature 2017 Aug 31; 548:592. PMID: 28858313 http://www.nature.com/nature/journal/v548/n7669/full/nature23664.html