To examine a potential role for phytoestrogens in postmenopausal bone loss, the oophorectomized (OOX) rat model has been used in three studies to investigate the effects of the phytoestrogens coumestrol, zearalanol and a mixture of isoflavones on estrogen-dependent bone loss. In the studies of coumestrol and zearalanol, the rats were allocated to a control group, a phytoestrogen-treated group (1.5 μmol coumestrol or 3.1 mmol zearalanol twice per week, intramuscular) or, in the coumestrol study, an estrogen-treated group (28.1 nmol, intramuscular). In the isoflavone study, the rats were allocated to a control group, an estrogen treated group or a treatment group that received 131.25 mg of phytoestrogens per week incorporated into the nonpurified rat diet. Bone mineral density was measured globally and at the spine and femur at base line and 6 wk post-oophorectomy. In the coumestrol study, blood and urine samples were collected. Compared with the control group, rats receiving coumestrol and zearalanol had significantly reduced bone loss at all sites measured. The estrogen-treated group had significantly greater bone density than the control and the coumestrol-treated groups in the spine and global measurements. Coumestrol reduced urine calcium excretion and the bone resorption markers pyridinoline and deoxypyridinoline after 1 wk of treatment. Oral isoflavone phytoestrogens had no effect on oophorectomized rats including bone loss at the dose used. Thus, for the first time, the bioactivity of coumestrol and zearalanol in preventing bone loss has been demonstrated in a well-recognized model of postmenopausal bone loss.

The use of induced Pluripotent Stem Cells (iPSC) as a source of autologous tissues shows great promise in regenerative medicine. Nevertheless, several major challenges remain to be addressed before iPSC-derived cells can be used in therapy, and experience of their clinical use is extremely limited. In this review, the factors affecting the safe translation of iPSC to the clinic are considered, together with an account of efforts being made to overcome these issues. The review draws upon experiences with pluripotent stem-cell therapeutics, including clinical trials involving human embryonic stem cells and the widely transplanted mesenchymal stem cells. The discussion covers concerns relating to: (i) the reprogramming process; (ii) the detection and removal of incompletely differentiated and pluripotent cells from the resulting medicinal products; and (iii) genomic and epigenetic changes, and the evolutionary and selective processes occurring during culture expansion, associated with production of iPSC-therapeutics. In addition, (iv) methods for the practical culture-at-scale and standardization required for routine clinical use are considered. Finally, (v) the potential of iPSC in the treatment of human disease is evaluated in the light of what is known about the reprogramming process, the behavior of cells in culture, and the performance of iPSC in pre-clinical studies.

Parkinson’s disease (PD) is a neurodegenerative disease associated with progressive death of midbrain dopamine (DAn) neurons in the substantia nigra (SN). Since it has been proposed that patients with PD exhibit an overall proinflammatory state, and since astrocytes are key mediators of the inflammation response in the brain, here we sought to address whether astrocyte-mediated inflammatory signaling could contribute to PD neuropathology. For this purpose, we generated astrocytes from induced pluripotent stem cells (iPSCs) representing patients with PD and healthy controls. Transcriptomic analyses identified a unique inflammatory gene expression signature in PD astrocytes compared with controls. In particular, the proinflammatory cytokine IL-6 was found to be highly expressed and released by PD astrocytes and was found to induce toxicity in DAn. Mechanistically, neuronal cell death was mediated by IL-6 receptor (IL-6R) expressed in human PD neurons, leading to downstream activation of STAT3. Blockage of IL-6R by the addition of the FDA-approved anti–IL-6R antibody, Tocilizumab, prevented PD neuronal death. SN neurons overexpressing IL-6R and reactive astrocytes expressing IL-6 were detected in postmortem brain tissue of patients at early stages of PD. Our findings highlight the potential role of astrocyte-mediated inflammatory signaling in neuronal loss in PD and pave the way for the design of future therapeutics.

Human pluripotent stem cells, such as embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), have the unique abilities of differentiation into any cell type of the organism (pluripotency) and indefinite self-renewal. Here, we show that the Rem2 GTPase, a suppressor of the p53 pathway, is up-regulated in hESCs and, by loss- and gain-of-function studies, that it is a major player in the maintenance of hESC self-renewal and pluripotency. We show that Rem2 mediates the fibroblastic growth factor 2 (FGF2) signaling pathway to maintain proliferation of hESCs. We demonstrate that Rem2 effects are mediated by suppressing the transcriptional activity of p53 and cyclin D₁ to maintain survival of hESCs. Importantly, Rem2 does this by preventing protein degradation during DNA damage. Given that Rem2 maintains hESCs, we also show that it is as efficient as c-Myc by enhancing reprogramming of human somatic cells into iPSCs eightfold. Rem2 does this by accelerating the cell cycle and protecting from apoptosis via its effects on cyclin D₁ expression/localization and suppression of p53 transcription. We show that the effects of Rem2 on cyclin D₁ are independent of p53 function. These results define the cell cycle and apoptosis as a rate-limiting step during the reprogramming phenomena. Our studies highlight the possibility of reprogramming somatic cells by imposing hESC-specific cell cycle features for making safer iPSCs for cell therapy use.