Human ESCs are a potential source of regenerative medicine. However, safety and efficacy of ESC derivatives must be validated strictly before clinical application. Wang et al. manufactured clinical-grade human parthenogenetic ESC-derived DA neurons under CGMP conditions. The authors found that transplantation of these DA cells into monkeys was safe and provided preclinical data for human ESC-based clinical trials.

DSG2 is a desmosomal cadherin molecule. In this article, Min and colleagues show that DSG2 is a valuable PSC surface marker that is essential for the maintenance of PSC self-renewal and pluripotency and the acquisition of pluripotency during somatic cell reprogramming through the regulation of β-catenin-mediated EMT signaling.

In this article, Kang and colleagues elucidate the critical function and regulatory mechanism of the miR-590/Acvr2a/Terf1 signaling pathway in modulating telomere elongation and pluripotency in pre-iPSCs. These findings not only determined the miR-590/Acvr2a/Terf1 axis on regulating both telomere elongation and pluripotency but also revealed an underlying mechanism pushing forward the maturation of the pre-iPSCs.

In this work, Spits and colleagues present an in-depth study of mtDNA variants in hPSCs. Early-passage hESCs carry few low-frequency variants, while higher variant loads are observed in late-passage hESCs and hiPSCs. The presence of variants is determined by the somatic or embryonic origin of the line and modulated by random drift, spontaneous mutagenesis, and clonal culture takeover.

Integration of stem cell-derived neurons (ESNs) into native cellular environment remains a major challenge. This research develops methods to study ESNs and brain nerve cells in the culture dish. ESNs form functional nerve connections with brain nerve cells in morphology, protein expression, and electrophysiology studies. The results are critical for stem cell-based neural pathway regeneration.

Pek and colleagues report that the expression of differentiation factor Rga is heterogeneous between germline stem cells (GSCs) in the Drosophila ovaries. Dsn (human homolog of SON) represses rga transcription and promotes GSC heterogeneity, which is important for GSC homeostasis.

(Stem Cell Reports 10, 1267–1281; April 10, 2018)

Retinoic acid is commonly used in culture to differentiate stem cells into neurons and has established neural differentiation functions in vivo in developing and adult organisms. In this issue of Stem Cell Reports, Mishra et al. (2018) broaden its role in stem cell functions, showing that retinoic acid is necessary for stem and progenitor cell proliferation in the adult brain.

The authors discuss both retrospective and prospective approaches to better understand a heterogeneous group of poor prognosis human breast cancers referred to as “basal-like” because they express features of both normal human basal and luminal mammary cells. They suggest that future progress in modeling these human cancers will require more comprehensive comparisons of histological as well as molecular findings.

Wolvetang and colleagues used CRISPR/Cas9 technologies to manipulate the copy number and expression of the amyloid precursor protein (APP) gene in Down syndrome and corresponding euploid pluripotent stem cells. They demonstrate that APP modulates the expression of a surprisingly large cohort of genes and dictates Aβ42/40 ratio and pyroglutamate-E3 foci but does not affect hyperphosphorylated forms of tau associated with Alzheimer disease or neuronal cell death of in vitro generated cortical neurons.

In this article, Liu and colleagues show that telomere rejuvenation links to reprogramming and pluripotency of CiPSCs. Moreover, crotonylation induced by crotonic acid facilitates telomere maintenance and enhances chemically induced reprogramming to pluripotency.

In this article, Slukvin and colleagues show that GATA2 transcription factor is dispensable for hemogenic endothelium (HE) specification and diversification. However, GATA2 is primarily needed for HE to undergo endothelial-to-hematopoietic transition. They also revealed differences in the GATA2-regulated network in HE and non-HE.

Ding and colleagues developed a broadly useful approach to study novel regulators involved in hepatic differentiation of human pluripotent stem cells, with a combination of reporter system construction, genome-wide CRISPR-Cas9-based genetic screening, and targeted chemical screening. Studies revealed HDAC3 as a key regulator in hepatic lineage determination.

Kaneko and colleagues describe the generation of CD4+ T helper clone-derived iPSCs and differentiation of the cells into T-lineage cells, which had molecular signatures and functional properties more consistent with group 1 innate lymphoid cells. CD4 transduction and CD40 ligand high population purification of the regenerated cells enhanced the antigen-specific adjuvant responses via dendritic cells in an antigen-specific manner.

In this article, Mishra and colleagues identify a critical role for retinoic acid (RA) signaling in adult hippocampal neural stem and progenitor cell (NSPC) proliferation via hypoxia inducible factor-1α. Using RA reporter mice and conditional disruption of RA signaling in adult NSPCs, the authors identify RA signaling in adult NSPCs and NSPC RA signaling is required for normal proliferative behavior.

In this article, Rustgi and colleagues identify a new population of long-lived cells within the intestinal crypt, marked by the Krt15 promoter. Krt15+ cells are self-renewing, multipotent, and radio-resistant cells that facilitate recovery from radiation-induced injury. Furthermore, such cells, when targeted with Apc loss, undergo transformation to adenomas and adenocarcinomas.

In this article, Kiskinis and coworkers use all-optical electrophysiology to characterize an iPSC-based model of ALS. By performing high-throughput optical measurements of excitability in motor neurons derived from patients with a SOD1 (A4V) mutations and genome-corrected controls, the authors identify differences in firing consistent with a deficit in KV7 current in the mutants.

Schroeder and colleagues show that GSK3 and MEK inhibition (2i) has several simultaneous effects on murine ESC cultures. They applied long-term time-lapse imaging to quantify cell death, proliferation, and Nanog expression dynamics in single ESCs. This demonstrated that 2i treatment of ESCs leads to more uniform and high Nanog expression due to both selective and inductive effects.

Medelnik and colleagues identify lysophosphatidic acid as a serum factor that has a major effect on the expansion of the apical domain of human ESC-derived neural progenitor cells, resulting in the formation of very large neural rosette-like structures that can be maintained for many passages in the absence of neuronal and glial differentiation if constantly supplied with LPA.

In this paper, Bertrand and colleagues show that kit signaling is necessary to the development of zebrafish hematopoietic stem cells, as well as for their expansion. Moreover, they characterize a new zebrafish cytokine, oncostatin M (osm), which acts upstream of kit signaling during HSC specification but synergizes with kitlgb to promote HSC expansion in the caudal hematopoietic tissue.