Česká Genetická Banka

SCIENCE: 30. 10. 2012

SCIENCE: ipsc disease modeling

"Induced pluripotent stem cell (iPSC) technology has provided previously unanticipated possibilities to model human disease in the culture dish. Reprogramming somatic cells from patients into an embryonic stem cell–like state (1) followed by differentiation into disease-relevant cell types can generate an unlimited source of human tissue carrying the genetic variations that caused or facilitated disease development (2). Yet, despite the excitement over this “disease-in-a-dish” approach, studying genetic disorders in patient-derived cells faces more challenges than studies using genetically well-defined model systems. Here we describe some of these limitations, and also present some solutions for ensuring that iPSC technology lives up to at least some of its promise."

http://www.sciencemag.org/content/338/6111/1155.summary

 

NATURE: Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells

"In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of toll-like receptor 3 (TLR3) immunity are prone to HSV-1 encephalitis (HSE)^{1, 2, 3}. We tested the hypothesis that the pathogenesis of HSE involves non-haematopoietic CNS-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of interferon-β (IFN-β) and/or IFN-λ1 in response to stimulation by the dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-λ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele showed that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was rescued further by treatment with exogenous IFN-α or IFN-β ( IFN-α/β) but not IFN-λ1. Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3-pathway deficiencies."

http://www.nature.com/nature/journal/v491/n7426/full/nature11583.html

NATURE: Self-renewal of embryonic-stem-cell-derived progenitors by organ-matched mesenchyme

"One goal of regenerative medicine, to use stem cells to replace cells lost by injury or disease, depends on producing an excess of the relevant cell for study or transplantation. To this end, the stepwise differentiation of stem cells into specialized derivatives has been successful for some cell types^{1, 2, 3}, but a major problem remains the inefficient conversion of cells from one stage of differentiation to the next. If specialized cells are to be produced in large numbers it will be necessary to expand progenitor cells, without differentiation, at some steps of the process. Using the pancreatic lineage as a model for embryonic-stem-cell differentiation, we demonstrate that this is a solvable problem. Co-culture with organ-matched mesenchyme permits proliferation and self-renewal of progenitors, without differentiation, and enables an expansion of more than a million-fold for human endodermal cells with full retention of their developmental potential. This effect is specific both to the mesenchymal cell and to the progenitor being amplified. Progenitors that have been serially expanded on mesenchyme give rise to glucose-sensing, insulin-secreting cells when transplanted in vivo. Theoretically, the identification of stage-specific renewal signals can be incorporated into any scheme for the efficient production of large numbers of differentiated cells from stem cells and may therefore have wide application in regenerative biology."

http://www.nature.com/nature/journal/v491/n7426/full/nature11463.html

NATURE: Misguided cancer goal

"An influential US advocacy group has set a deadline to beat breast cancer by 2020. But it puts public trust at risk by promising an objective that science cannot yet deliver."

http://www.nature.com/news/misguided-cancer-goal-1.11894