Current Stem Cell Reports最新文献

Purpose of review: Hematopoietic stem cells (HSCs) are reliant on intrinsic and extrinsic factors for tight control of self-renewal, quiescence, differentiation, and homing. Given the intimate relationship between HSCs and their niche, increasing numbers of studies are examining how biophysical cues in the hematopoietic microenvironment impact HSC functions.

Recent findings: Numerous mechanosensors are present on hematopoietic cells, including integrins, mechanosensitive ion channels, and primary cilia. Integrin-ligand adhesion, in particular, has been found to be critical for homing and anchoring of HSCs and progenitors in the bone marrow. Integrin-mediated interactions with ligands present on extracellular matrix and endothelial cells are key to establishing long-term engraftment and quiescence of HSCs. Importantly, disruption in the architecture and cellular composition of the bone marrow associated with conditioning regimens and primary myelofibrosis exposes HSCs to a profoundly distinct mechanical environment, with potential implications for progression of hematologic dysfunction and pathologies.

Summary: Study of the mechanobiological signals that govern hematopoiesis represents an important future step toward understanding HSC biology in homeostasis, aging, and cancer.

Purpose of review: Virus-associated malignancies are a global health burden, constituting 10-12% of cancers worldwide. As these tumors express foreign viral antigens that can elicit specific T cell responses, virus-directed immunotherapies are a promising treatment strategy. Specifically, adoptive cell transfer of virus-specific T cells (VSTs) has demonstrated the potential to eradicate cancers associated with certain viruses.

Recent findings: Initial studies in 1990s first showed that VSTs specific for the Epstein-Barr virus (EBVSTs) can induce complete remissions in patients with post-transplant lymphoproliferative disease. Since then, studies have validated the specificity and safety of VSTs in multiple lymphomas and solid malignancies. However, challenges remain to optimize this platform for widespread use, including enhancing potency and persistence, overcoming the immunosuppressive tumor microenvironment, and streamlining manufacturing processes that comply with regulatory requirements.

Summary: This review focuses on data from clinical trials evaluating VSTs directed against three viruses (EBV, HPV and MCPyV), as well as recent preclinical and clinical advances, and potential future directions.

Purpose of review: Continued development of gene editing techniques has raised the real possibility of clinical application of germline gene editing. These results, as well as reports of an unethical experiment which resulted in the birth of at least two children from edited embryos in 2018, have highlighted the urgency and importance of ethical issues about translational pathways for editing of human germline cells. Charting responsible translational pathways for germline gene editing requires tackling some significant and complex ethical issues.

Recent findings: A literature on development of clinical applications of germline gene editing is emerging, and several key ethical issues are coming into focus as major challenges for responsible translational pathways.

Summary: Potential clinical utility, clinical justification, and human subjects research for germline gene editing raise outstanding ethical questions. Work on these questions will help provide guidance to researchers and clinicians and direct translational projects toward justifiable applications.

Purpose of review: Inflammatory signals have emerged as critical regulators of hematopoietic stem cell (HSC) function. Specifically, HSCs are highly responsive to acute changes in systemic inflammation and this influences not only their division rate but also their lineage fate. Identifying how inflammation regulates HSCs and shapes the blood system is crucial to understanding the mechanisms underpinning these processes, as well as potential links between them.

Recent findings: A widening array of physiologic and pathologic processes involving heightened inflammation are now recognized to critically affect HSC biology and blood lineage production. Conditions documented to affect HSC function include not only acute and chronic infections but also autoinflammatory conditions, irradiation injury, and physiologic states such as aging and obesity.

Summary: Recognizing the contexts during which inflammation affects primitive hematopoiesis is essential to improving our understanding of HSC biology and informing new therapeutic interventions against maladaptive hematopoiesis that occurs during inflammatory diseases, infections, and cancer-related disorders.

Purpose of review: Throughout the lifespan, lung injury impedes the primary critical function essential for life-respiration. To repair quickly and efficiently is critical and is orchestrated by a diverse repertoire of progenitor cells and their niche. This review incorporates knowledge gained from early studies in lung epithelial morphogenesis and cell fate and explores its relevance to more recent findings of lung progenitor and stem cells in development and regeneration.

Recent findings: Cell fate in the lung is organized into an early specification phase and progressive differentiation phase in lung development. The advent of single cell analysis combined with lineage analysis and projections is uncovering new functional cell types in the lung providing a topographical atlas for progenitor cell lineage commitment during development, homeostasis, and regeneration.

Summary: Lineage commitment of lung progenitor cells is spatiotemporally regulated during development. Single cell sequencing technologies have significantly advanced our understanding of the similarities and differences between developmental and regenerative cell fate trajectories. Subsequent unraveling of the molecular mechanisms underlying these cell fate decisions will be essential to manipulating progenitor cells for regeneration.

Purpose of review: Prenatal stem cell and gene therapy approaches are amongst the few therapies that can promise the birth of a healthy infant with specific known genetic diseases. This review describes fetal immune cell signaling and its potential influence on donor cell engraftment, and summarizes mechanisms of central T cell tolerance to peripherally-acquired antigen in the context of prenatal therapies for Hemophilia A.

Recent findings: During early gestation, different subsets of antigen presenting cells take up peripherally-acquired, non-inherited antigens and induce the deletion of antigen-reactive T-cell precursors in the thymus, demonstrating the potential for using prenatal cell and gene therapies to induce central tolerance to FVIII in the context of prenatal diagnosis/therapy of Hemophilia A.

Summary: Prenatal cell and gene therapies are promising approaches to treat several genetic disorders including Hemophilia A and B. Understanding the mechanisms of how FVIII-specific tolerance is achieved during ontogeny could help develop novel therapies for HA and better approaches to overcome FVIII inhibitors.