Induced Pluripotent Stem Cells Generated from Patients with ALS Can Be Differentiated into Motor Neurons

July 2008- This study examined a patient with ALS disease. In the study, human iPS cells were generated from an 82-year-old woman with ALS disease, which were then “direct differentiated into those neural cells destroyed by ALS,” demonstrating promise for patient-specific cell therapy and showing that iPS cells can be produced from elderly individuals stricken afflicted with a chronic disease (Dimos et al, 2008).

Induced pluripotent stem cell lines derived from human somatic cells

Induced pluripotent stem cell lines derived from human somatic cells

December 2007- The authors of this study proved that it was possible to return somatic cell nuclei to an undifferentiated state by introducing Oct4, Sox2, Nanog, and Lin28. These four factors were sufficient to induce pluripotency in human somatic cells. The normal karyotypes, expression of telomerase activity, expression of cell surface markers and genes characterized in human ES cells, and potential of iPS cells to develop into cells formed by any of the three germ layers proved their pluripotency and similarity to ES cells (Yu et al., 2007).

Generation of germline-competent induced pluripotent stem cells.

Generation of germline-competent induced pluripotent stem cells

June 2007- Building on the previous study by Takahashi and Yamanaka, Okita et al. demonstrated that “selection for Nanog expression results in germline-competent iPS cells” that had many more similarities to ES cells in terms of gene expression and DNA methylation patterns. They were able to obtain adult chimeras from seven Nanog iPS cell clones. This experiment also demonstrated that the retroviral introduction of c-Myc should be avoided, as it was linked to the formation of tumors (Okita et al. 2007).

Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors.

August 2006- Takahashi and Yamanaka introduced four factors, Oct3/4, Sox2, c-Myc, and Klf4, into mouse embryonic or adult fibroblasts. These cells were deemed to be pluripotent because they displayed “the morphology and growth properties of ES cells and express[ed] ES cell marker genes.” Additionally, the iPS cells formed teratoma tumors when injected into mice, and when injected into blastocysts, they “contributed to mouse embryonic development.” Therefore, pluripotency could be induced in mouse embryonic and adult fibroblasts by the introduction of four factors (Takahashi and Yamanaka 2006).

Nuclear Reprogramming of Somatic Cells After Fusion with Human Embryonic Stem Cells.

August 2005- In this study, Cowan, Atienza, Melton, and Eggan reprogram somatic cells to an embryonic state by fusing human embryonic stem (hES) cells with human fibroblasts. Their “morphology, growth rate, and antigen expression patterns” were “characteristic of hES cells” (Cowan et al., 2005). This experiment showed that “human embryonic stem cells are able to reprogram the nuclei of fully differentiated human somatic cells, apparently conferring on them a pluripotent state” (Surani 2005).

Embryonic Stem Cell Lines Derived From Human Blastocysts

November 1998- Two separate groups report their success growing human stem cells in culture.

Dr. James Thomson (University of Wisconsin, Madison) reports derivation of human embryonic stem cells. He used cells derived from human embryos created in vitro, while Dr. John Gearhart (Johns Hopkins University) used stem cells from aborted fetal tissue. The two scientists placed these cells into a mouse cell feeder layer so that the culture would continue to grow indefinitely. The resulting cel lines "produce the enzyme telomerase, which resets the cells' chromosomal clocks" preventing an early death and allowing them to be cultured indefinitely ("The Stem Cell Debate"). Dr. Timothy Kamp generated a difficult to obtain cell type when he differentiates human ES cells into human cardiomyocytes (“Induced Pluripotent Stem (iPS) Cells”).

Viable offspring derived from fetal and adult mammalian cells

July 5,1996- Dolly the sheep is cloned from adult stem cells by the Roslin Institute in Scotland and PPL Therapeutics. Dolly was cloned when Ian Wilmut, Keith Campbell, and their team of scientists transferred the nucleus of adult udder cells from a 6 year old Finn Dorset ewe into an unfertilized enucleated sheep egg. The nucleus and egg were fused together with an electric current to ensure the egg had a complete set of chromosomes, cultured in vitro, and then implanted into the uterus of a third sheep who brought Dolly to term (“Stem Cells”).

Discovery by Embryologist Leroy Stevens: Pluripotent Embryonic Stem Cells

A teratoma tumor

In 1958, one of the earliest steps towards the discovery of iPS cells occurred when embryologist Leroy Stevens discovered a large tumor on the testes of a mouse. The tumor was composed of many different mouse parts from all three germ layers, including muscle, skin, teeth, bone, and hair. After transplanting bits of the tumor into healthy mice, he observed that some of the bits developed into varied cell and tissue types, while groups of undifferentiated cells also formed. Stevens publishes his results, asserting that the cells from inside the tumor were pluripotent, a sort of cancerous embryonic cell (“Stem Cells”).

Stem Cell Timeline References

Cowan, C.A., Atienza, J., Melton, D.A., and Eggan, K. (2005). Nuclear Reprogramming of Somatic Cells After Fusion with Human Embryonic Stem Cells. Science 309, 1369-1373.

Dimos, J.T., et al. (2008). Induced Pluripotent Stem Cells Generated from Patients with ALS Can Be Differentiated into Motor Neurons. Science 321, 1218-1221.

“Induced Pluripotent Stem (iPS) Cells.” Cellular Dynamics International. 2008. Cellular Dynamics International. 16 November 2008 .

Okita, K., Ichisaka, T., and Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature 448, 313-317.

Scott, C.T. (2006). Stem Cell Now (New York: Pi Press).

“Stem Cells.” Garland Science: Taylor & Francis Group. 2006. Garland Science Publishing. 20 November 2008. .

Surani, M. (2005). Nuclear Reprogramming by Human Embryonic Stem Cells. Cell 122, 653-654.

Takahashi, K., and Yamanaka, S. (2006). Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell 126, 663-676.

Yu, J., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318 1917-1920.