In the August 19th online edition of Cell Stem Cell, J. Tchieu et al. from the UCLA School of Medicine reported their study results on epigenetic modication and X chromosome inactivation in human reprogrammed fibroblasts. The investigators noted that reprogramming of female mouse cells results in reactivation of the inactive X chromosome (Xi). However, the researchers found that in human induced pluripotent stem cells (hiPSCs) several of the female cell lines carried the inactive X chromosome. The experimental data revealed that Xi chromatin did undergo some epigenetic modifications since there was only partial loss of the XIST transcripts as opposed to female human embryonic stem cell lines in which exhibit two active X chromosomes. Additionally, the human female fibroblasts are mosaics for Xi, whereas hiPSCs are clonal. The authors noted that "the nonrandom pattern of X chromosome inactivation in female hiPSCs, which is maintained upon differentiation, has critical implications for clinical applications and disease modeling, and could be exploited for a unique form of gene therapy for X-linked diseases."

In the July 19th online edition of Nature, K. Kim et al. from Harvard Medical School reported their findings on methylation patterns in low-passage induced pluripotent stem cells (iPSCs). The experimental results revealed that murine iPSCs which were derived from trancription factor-based reprogramming still retain some of the methylation characteristics of their somatic tissue origin. The DNA methylation signature in these iPSCs had restricted cell fates and favored downstream differentiation into tissue lineages related to the unprogrammed donor cell. The investigators found from their experimental data that this epigenetic memory could be reset by differentiation and serial reprogramming as well as by using chromatin-modifying drugs. Additionally, pluripotent stem cells derived by somatic cell nuclear transfer had methylation patterns closely resembling "classical" embryonic stem cells. The authors concluded that their study results demonstrated that "nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modeling or treatment."

In the August 16th online edition of Stem Cells, A. Swistowski et al. from the Buck Institute for Age Research (Novato, CA) reported their experimental results in generating in vitro functional dopaminergic neurons from human induce pluripotent stem cells (iPSCs). With the same culture conditions for growing and differentiating human embryonic stem cells (hESCs), the investigators used two iPSC human cell lines to demonstrate expansion and differentiation of the iPSCs into committed neural stem cells (NSCs) and dopaminergic neurons. In order to demonstrate functionality of the differentiated iPSCs in vivo, the researchers used a Parkisonian rat model in which the cells were transplanted into the brain of an 6-OHA-treated (6-hydroxydopamine) rats. The animals receiving the transplanted cells were reported to survive the procedure and with improved behavioral responses. The researchers also conducted genome-wide microarray comparisons between hESCs and iPSCs derived NSC and dopaminergic neurons and found no differences at the molecular level. The authors concluded that the ability to use iPSCs to generate dopaminergic neurons can be used in the future for treating patients with Parkinson's Disease.

In the August 13th issue of J. Biological Chemistry, G. Liang et al. from the University of North Carolina reported their experimental results on the use of butyrate to enhance reprogramming of mouse fibroblasts into induced pluripotent stem cells (iPSCs). The investigators noted that butyrate is a natural small fatty acid that inhibits histone deacetylation. The experimental results demonstrated that butyrate can increase the efficiency in generating mouse iPSCs which had been transfected with the four genes encoding the transcription factors Oct4, Klf4, Sox2, and c-Myc. Additionally, the researchers conducted experiments to showed that butyrate-enhanced reprogramming efficiencies is mediated by c-Myc during the early stages of reprogramming. Genome-wide gene expression analysis on butyrate-transfected mouse embryonic fibroblast cells revealed upregulation of genes embryonic-associated genes during reprogramming. The authors concluded that their study results "identifies butyrate as a chemical factor capable of promoting iPS cell generation."

In the August 6th issue of Cell, M. Ieda et al. from the University of California, San Francisco reported their experimental results in which they were able to reprogram postnatal cardiac or dermal fibroblasts directly into cardiomyocytes. The investigators used three developmental transcription factors (i.e. Gata4, Mef2c, and Tbx5) for generating induced cardiomyocytes (iCMs). The iCMs expressed cardiac-specific markers, contracted spontaneously, and its global gene expression profile was similar to cardiomyocytes isolated from mice. The investigators also reported that iCMs derived from fibroblasts differentiated in vivo into cardiomyocyte-like cells one day after transduction of the transcription factors and transplanted into the mouse hearts. The authors concluded that their observations "demonstrate that functional cardiomyocytes can be directly reprogrammed from differentiated somatic cells by defined factors."

In the July issue of Cell Transplantation, Australian scientists P. A. Tat et al. from the Monash institute of Medical Research (Melbourne) reported their experimental results on the transduction/reprogramming efficiencies in either mouse neural stem cells (NSCs), adipose tissue-derived cells (ADCs), or mouse embryonic fibroblasts (mEFs) for generating induced pluripotent stem (iPS) cells. With a retroviral vector encoding for the DNA sequence of Oct4, Sox2, Klf4, and c-Myc, the investigators transduced NSCs, ADCs, and mEFs and analyzed GFP expression as an indicator of reprogramming (GFP transgene was under the control of the Oct4 promoter). Although the transduction efficiencies were similar for all 3 cell types, the investigators found that reprogramming efficiencies in the number of GFP-positive colonies for both NSCs and ADCs were greater than control mEFs. Additionally, the experimental results revealed that ADCs had an 8- and 38-fold increase in reprogramming efficiencies compared to NSCs and mEFs, respectively. In vitro and in vivo experiments showed that iPS cells from ADCs were found to be pluripotent by their ability to differentiate into cell lineages representing all 3 germ layers. The authors concluded from their study results "that ADCs are an ideal candidate as a readily accessible somatic cell type for high efficiency and establishment of iPS cell lines."

In the July 7th online edition of PNAS, Z. Alipio et al. from SUNY at Stony brook reported their proof of concept studies in which they were able to reprogram mouse somatic cells and differentiate the induced pluripotent stem cells (iPSCs) into insulin-secreting β-like cells. The investigators demonstrated in vitro that iPSC-derived β-like cells, similar to endogenous insulin-secreting mouse cells, were able to secrete insulin in response to the presence of glucose. When the iPSC-derived β-like cells were transplanted into type 1 and 2 diabetic mice, the differentiated β-like cells were able to secrete insulin and with normal gylcemic controls in glucose tolerance experiments. Hemoglobin A1c and blood glucose levels were found to be at normal levels 3 months after transplantation; illustrating long-term correction of hyperglycemia by the β-like cells . The authors concluded that the data from their study illustrate the "potential clinical application of reprogrammed somatic cells in the treatment of diabetes type 1 and 2."

In the June 22nd online edition of Stem Cells, S. Ron-Bigger et al from The Hebrew University of Jerusalem conducted a study on reprogramming somatic cells which took some of the air out of using induced pluripotent stem cells (iPSCs) as an alternative to embryonic stem cells for future cell-based therapeutic applications. The investigators published their study results demonstrating that resetting the epigenetic memory of somatic cells can lead to abnormal epigenetic changes and pathological conditions. Studying the fate of the silenced tumor suppressor gene, p16 (CDKN2A), during reprogramming. Surprisingly, the researchers reported that reprogramming restored p16 expression, irrespective of whether the cells were induced to differentiate. Large scale methylation profiling of donor cells identified hundreds of aberrant methylation sites. On the positive side, many of these sites had restored normal methylation patterns following reprogramming. The authors concluded that "reprogramming approaches may be applied to repair the epigenetic lesions associated with cancer."

In the June 16th online edition of the Journal of Dental Research, N. Tamaoki et al. from Kyoto University (Japan) reported their experimental results using dental pulp cells (DPCs) for reprogramming and generating induced pluripotent stem cells (iPSCs). The study rationale was based on obtaining an easily accessible source of human cells using a minimally invasive procedure. The investigators used DPCs, which are easily obtainable from extracted, for ex vivo expansion. From 6 cell lines, the researchers were able to generate iPSCs from 5 of the DPC lines using 3 or 4 transcription factors typically used for reprogramming. Surveying 107 DPC lines, the experimental results revealed 2 cell lines were homozygous for all 3 HLA loci. The authors concluded that the 2 iPSC lines would be a perfect match for approximately 20% of the Japanes population and DPCs could serve as a source for human cells in establishing iPS cell banks for use in regenerative medicine.

In a paper published in the June 2 online edition of Stem Cells, Chinese scientists from the Shanghai Institutes for Biological Sciences, T. Chen et al., demonstrated the importance in E-cadherin expression during reprogramming of somatic cells. By screening a chemical library, the investigators found upregulation of E-cadherin significantly enhanced reprogramming efficiencies in order to establish induced pluripotent stem (iPS) cells. Additionally, the researchers confirmed their observation in which knockdown experiments of endogenous E-cadherin expression with shRNA resulted in reduced reprogramming efficiencies in generating iPS cells. Similarly, inhibiting cell-cell contact by inhibitory peptide or neutralizing antibody to E-cadherin reduced the ability to form iPS cells. The authors concluded that "adhesive binding of E-cadherin" between the cells is required for reprogramming and "suggest new routes for more efficient iPS cell generation.