Current Stem Cell Reports最新文献

Purpose of the review: Blood specification is a highly dynamic process, whereby committed hemogenic endothelial cells (ECs) progressively transdifferentiate into multipotent, self-renewing hematopoietic stem cells (HSCs). Massive changes in gene expression must occur to switch cell identity, however the factors that mediate such an effect were a mystery until recently. This review summarizes the higher-order mechanisms involved in endothelial to hematopoietic reprogramming identified thus far.

Recent findings: Accumulating evidence from mouse and zebrafish studies reveal that numerous chromatin-modifying (epigenetic) and RNA-modifying (epitranscriptomic) factors are required for the formation of HSCs from hemogenic endothelium. These genes function throughout the endothelial-hematopoietic transition, suggesting a dynamic interplay between 'epi'-machineries.

Summary: Epigenetic and epitranscriptomic regulation are key mechanisms for reshaping global EC gene expression patterns to those that support HSC production. Future studies that capture modification dynamics should bring us closer to a complete understanding of how HSCs transition from hemogenic endothelium at the molecular level.

Purpose of review: Recent advancements in the use of genetically modified hematopoietic stem cells (HSCs) and the emergent use of chimeric antigen receptor (CAR) T-cell immunotherapy has highlighted issues associated with the use of genetically engineered cellular products. This review explores some of the challenges linked with translating the use of genetically modified cells.

Recent findings: The use of genetically modified HSCs for ADA-SCID now has European approval and the U.S. Food and Drug Administration recently approved the use of CAR-T cells for relapsed/refractory B-cell acute lymphoblastic leukemia. Current good manufacturing processes have now been developed for the collection, expansion, storage, modification, and administration of genetically modified cells.

Summary: Genetically engineered cells can be used for several therapeutic purposes. However, significant challenges remain in making these cellular therapeutics readily available. A better understanding of this technology along with improvements in the manufacturing process is allowing the translation process to become more standardized.

Purpose of review: Recent developments in regenerative medicine have precipitated the need to expand gene-modified human T cells to numbers that exceed the capacity of well-plate-based, and flask-based processes. This review discusses the changes in process development that are needed to meet the cell expansion requirements by utilizing hollow-fiber bioreactors. Maintenance of cell proliferation over long periods can become limited by unfilled demands for nutrients and oxygen and by the accumulation of waste products in the local environment.

Recent findings: Perfusion feeding, improved gas exchange, and the efficient removal of lactate can increase the yield of T cells from an average of 10.8E +09 to more than 28E +09 in only 10 days.

Summary: Aggressively feeding cells and actively keeping cells in the bioreactor improves gas exchange and metabolite management over semi-static methods. The ability to remove the environmental constraints that can limit cell expansion by using a two-chamber hollow-fiber bioreactor will be discussed.

Purpose of review: The '14-day rule', which limits research on human embryos to the first 14 days after fertilisation, has long been a pillar of regulation in this contested area. Recently, advances in developmental biology have led to calls to rethink the rule and its application. In this paper, I address the question of whether the 14-day rule should be replaced and, if so, how.

Recent findings: The two lines of research that have prompted this question are new techniques enabling culture of embryos at least up to 14 days and patterning experiments with pluripotent cells suggesting that they might form embryo-like structures. I consider each of these in relation to the foundations and function of the rule to examine whether they warrant change.

Summary: I argue that the 14-day rule for embryo research should be open to change, but that this possibility must be addressed through early and thorough discussion involving a wide range of publics and other stakeholders.

Purpose of review: This review will discuss how the steroid hormones, estrogen and progesterone, as well as treatments that target steroid receptors, can regulate cancer stem cell (CSC) activity. The CSC theory proposes a hierarchical organization in tumors where at its apex lies a subpopulation of cancer cells endowed with self-renewal and differentiation capacity.

Recent findings: In breast cancer (BC), CSCs have been suggested to play a key role in tumor maintenance, disease progression, and the formation of metastases. In preclinical models of BC, only a few CSCs are required sustain tumor re-growth, especially after conventional anti-endocrine treatments. CSCs include therapy-resistant clones that survive standard of care treatments like chemotherapy, irradiation, and hormonal therapy.

Summary: The relevance of hormones for both normal mammary gland and BC development is well described, but it was only recently that the activities of hormones on CSCs have been investigated, opening new directions for future BC treatments and CSCs.

Purpose of review: In this review, we aim to discuss the role of the bone marrow microenvironment in supporting hematopoiesis, with particular focus on the contribution of the endothelial niche in dictating hematopoietic stem cell (HSC) fate.

Recent findings: Evidence gathered in the past two decades revealed that specific cell types within the bone marrow niche influence the hematopoietic system. Endothelial cells have emerged as a key component of the HSC niche, directly affecting stem cell quiescence, self-renewal, and lineage differentiation. Physiological alterations of the bone marrow niche occurring in aging have been described to be sufficient to promote functional aging of young HSCs. Furthermore, a growing body of evidence suggests that aberrant activation of endothelial-derived signaling pathways can aid or trigger neoplastic transformation.

Summary: Several groups have contributed to the characterization of the different cell types that comprise the complex bone marrow environment, whose function was long perceived as an undiscernible sum of many parts. Further studies will need to uncover niche cell-type-specific pathways, in order to provide new targets and therapeutic options that aim at withdrawing the microenvironmental support to malignant cells while sparing normal HSCs.

Purpose of review: Interferon-gamma (IFN-γ) is a pro-inflammatory cytokine that participates in the regulation of hematopoietic stem cells (HSC) during development and under homeostatic conditions. IFN-γ also plays a key pathogenic role in several diseases that affect hematopoiesis including aplastic anemia, hemophagocytic lymphohistiocytosis, and cirrhosis of the liver.

Recent findings: Studies have shown that increased IFN-γ negatively affects HSC homeostasis, skewing HSC towards differentiation over self-renewal and eventually causing exhaustion of the HSC compartment.

Summary: Here, we explore the mechanisms by which IFN-γ regulates HSC in both normal and pathological conditions. We focus on the role of IFN-γ signaling in HSC fate decisions, and the transcriptional changes it elicits. Elucidating the mechanisms through which IFN-γ regulates HSCs may lead to new therapeutic options to prevent or treat adverse hematologic effects of the many diseases to which IFN-γ contributes.