Search

The role of nucleolar phase separation in stem cell fate decision is not well understood. Here, the authors show that the nucleolus-localized LIN28A protein undergoes LLPS in mESCs and in vitro, and that pluripotency state conversion depends on this phase separation capacity.

A technique called somatic-cell nuclear transfer has been applied to human oocytes, resulting in the generation of personalized stem cells, albeit genetically abnormal ones. Two experts discuss the biomedical significance of this work and the ethical issues surrounding the use of human oocytes in research. See Article p.70

Six scientists in the field of stem cell research comment on our basic understanding of stem cells and other pluripotent cells, on their potential therapeutic use and on key challenges that remain.

Haematopoietic stem and progenitor cell conversion of human pluripotent stem cell-derived haemogenic endothelium.

This study uses single-cell expression profiling of pluripotent stem cells after various perturbations, and uncovers a high degree of variability that can be inherited through cell divisions—modulating microRNA or external signalling pathways induces a ground state with reduced gene expression heterogeneity and a distinct chromatin profile.

The production of haematopoietic stem cells is repressed during early mammalian embryogenesis by an epigenetic mechanism that involves the action of the Polycomb protein EZH1.

George Daley and John Rinn and colleagues identify large intergenic non-coding RNAs that are upregulated during reprogramming of induced pluripotent stem cells, and they show a functional role for large intergenic non-coding RNA-RoR in induced pluripotent stem cell derivation.

Inhibition of DOT1L, the H3K79 histone methyltransferase, increases cell reprogramming and substituted for KLF4 and c-Myc, showing that chromatin-modifying enzymes act not only as facilitators but also as barriers to reprogramming.

George Daley and colleagues show that Lin28 and Lin28B promote cellular transformation by repressing let-7 family members, leading to derepression of let-7 targets. They also find that LIN28 and LIN28B are overexpressed in ∼15% of primary human tumors and cancer cell lines and that their expression is associated with aggressive disease and poor prognosis across multiple tumor types.

George Daley and colleagues show that ectopic Ras activation diverts embryonic stem cells towards trophoblastic fates, and conversely, that inhibition of MAPK signaling reduces trophectoderm outgrowth from embryo explants. These results implicate Ras-MAPK signaling in this early and critical cell fate decision.

George Daley and colleagues show that transgenic mice expressing elevated levels of Lin28a have increased body size and delayed onset of puberty. These findings support human association studies implicating the LIN28B locus in height variation and timing of menarche.

Induced pluripotent stem cells (iPSCs) – whereby a patient's somatic cells are reprogrammed into an embryonic pluripotent state by the forced expression of a defined set of transcription factors – have the potential to transform drug discovery and development. In this article, Daley and colleagues discuss recent advances and current challenges associated with the generation and use of iPSCs.

Mouse induced pluripotent stem (iPS) cells have been shown to retain an epigenetic 'memory' of their cell type of origin. Kim et al. study this question in human cells and document both incomplete erasure of methylation and aberrant de novo methylation during reprogramming.

Andrew Feinberg and colleagues show that differential methylation of CpG island shores distinguish human induced pluripotent stem cells from the fibroblasts from which they were derived. These differentially methylated regions of the genome can also distinguish normal colon tissue from colorectal cancer.

Thanks to improved functional assays and more effective protocols for directed tissue differentiation, pluripotent stem cells are proving increasingly useful for uncovering the genetic and epigenetic basis of monogenic and complex diseases, and for investigating the functional consequences of genetic variation.

Daley and colleagues report that MAPK signalling controls pluripotency in embryonic stem cells and during somatic cell reprogramming by enhancing the stability and effects of LIN28 on direct mRNA targets through its phosphorylation by ERK.

The authors perform meta-analysis of GWAS studies for asthma from multiancestral cohorts. They identify five new loci and find that the asthma-associated loci are enriched near enhancer marks in immune cells.

Lummertz da Rocha et al. present CellComm, an algorithm that analyses cell–cell communication to predict signalling and regulatory networks, and identify regulators of haematopoietic development in the aorta–gonad–mesonephros region.

The role of the nucleolus in cell fate is not well known. Here the authors show nucleolar integrity maintained by rRNA-mediated liquid-liquid phase separation and 3D chromatin structure of perinucleolar heterochromatin regulates the fate transition of mouse embryonic stem cells to 2 cell-stage embryo-like cells, and that rRNA biogenesis regulates the 2-cell-to-4-cell transition of development.

Disparate modes of suppression of the let-7 microRNA family are selectively and inversely related in neuroblastoma.

The haematopoietic stem cells that rejuvenate blood depend on a dietary source of the amino acid valine — a finding that has been exploited to reduce the toxicity of bone-marrow transplantation in mice.

Nephrogenesis ceases after postnatal day 2 in the mouse or after the 36th week of gestation in humans, but how this is regulated is unclear. Here, the authors identify a role for the RNA-binding protein Lin28 and suppression of let-7 microRNA in regulating the duration of nephrogenesis.

Substitution of the active site gatekeeper residue in the BCR-ABL oncoprotein and related kinases is a common mechanism of imanitib resistance but has also been observed in drug-naïve patients. New work suggests that this residue stabilizes a hydrophobic spine that links the N and C kinase lobes, promoting the active conformation, and that adverse mutations at the gatekeeper residue further stabilize the spine. Disruption of the spine would be an attractive new goal in drug development.

Cellular reprogramming to a stem-cell state has now been achieved in tissues of genetically engineered mice. This work signals a future for regenerative medicine in which tissue fates might be manipulated in living organisms. See Article p.340

An international survey of human embryonic stem cell lines provides a benchmark for comparing results across laboratories.

Pluripotent stem cell lines differ in their capacity to differentiate into desired cell typesin vitro. Genetic and epigenetic variations contribute to functional variability between cell lines and heterogeneity within single clones. Characterizing such variations is important for the use of pluripotent stem cells in disease modelling and developmental processes and for their applications in regenerative medicine.

An advanced CellNet pipeline models the dynamics of stem cell differentiation.

This paper reports the ability to isolate human donor biopsies and use transcription factors to derive induced Pluripotent Stem (iPS) cells from fetal, neonatal, and adult human primary cells, including dermal fibroblasts isolated from a skin biopsy of a healthy adult volunteer. The human iPS cells resembled embryonic stem cells in their morphology and gene expression. These data establish a method to isolate iPS cells from patients, suggesting that it may be possible to use this procedure to isolate patient-specific cells in culture.

This Resource presents an atlas classifying the age-related changes in human hematopoietic stem and progenitor cells from gestation through aging.

Following initiation of the heartbeat in vertebrate embryos, cells lining the aorta, the placental vessels, and the umbilical and vitelline arteries begin to form haematopoietic cells. Here it is shown that biochemical forces imposed on the vascular wall at this developmental stage strongly influence development of early blood cells and that abrogation of nitric oxide—a mediator of shear-stress-induced signalling—compromises haematopoietic potential in vitro and in vivo.

Activation of dectin-1-dependent signaling in macrophages through ligation by galectin 9 promotes an immunosuppressive, protumorigenic microenvironment in pancreatic adenocarcinoma (PDA). Blocking dectin 1 ligation restores anti-tumor immunity and delays tumor growth, thus offering a novel strategy for improving the effectiveness of immunotherapy in patients with PDA.

Pluripotent stem cells can be generated in the laboratory through somatic cell nuclear transfer (generating nuclear transfer embryonic stem cells, ntESCs) or transcription-factor-based reprogramming (producing induced pluripotent stem cells, iPSCs). These methods reset the methylation signature of the genome — but to what extent? Here it is found that mouse iPSCs 'remember' the methylation status of their tissue of origin, but the methylation of ntESCs is more similar to that of naturally produced ES cells.

Here, iPS cell technology is used to study the mechanisms underlying dyskeratosis congenita in humans. Reprogramming restores telomere elongation in dyskeratosis congenita cells despite genetic lesions affecting telomerase. The reprogrammed cells were able to overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal, and multiple telomerase components are targeted by pluripotency-associated transcription factors.

Adult bone marrow contains numerous adipocytes, the numbers of which correlate inversely with the haematopoietic activity of the marrow. It had been unclear whether adipocytes participate in haematopoietic regulation or simply expand to fill marrow space; here it is shown that murine haematopoiesis is reduced in adipocyte-rich marrow during homeostasis, and that adipocytes antagonize haematopoietic recovery after bone-marrow irradiation.