Cold Spring Harbor perspectives in medicine最新文献

Changes in mitochondrial function play a critical role in the basic biology of aging and age-related disease. Mitochondria are typically thought of in the context of ATP production and oxidant production. However, it is clear that the mitochondria sit at a nexus of cell signaling where they affect metabolite, redox, and energy status, which influence many factors that contribute to the biology of aging, including stress responses, proteostasis, epigenetics, and inflammation. This has led to growing interest in identifying mitochondrial targeted interventions to delay or reverse age-related decline in function and promote healthy aging. In this review, we discuss the diverse roles of mitochondria in the cell. We then highlight some of the most promising strategies and compounds to target aging mitochondria in preclinical testing. Finally, we review the strategies and compounds that have advanced to clinical trials to test their ability to improve health in older adults.

The transition from a single, initiated cell to a full-blown malignant tumor involves significant genomic evolution. Exposure to carcinogens-whether directly mutagenic or not-can drive progression toward malignancy, as can stochastic acquisition of cancer-promoting genetic events. Mouse models using both carcinogens and germline genetic manipulations have enabled precise inquiry into the evolutionary dynamics that take place as a tumor progresses from benign to malignant to metastatic stages. Tumor progression is characterized by changes in somatic point mutations and copy-number alterations, even though any single tumor can itself have a high or low burden of genomic alterations. Further, lineage-tracing, single-cell analyses and CRISPR barcoding have revealed the distinct clonal dynamics within benign and malignant tumors. Application of these tools in a range of mouse models can shed unique light on the patterns of clonal evolution that take place in both mouse and human tumors.

Cell-replacement therapies are a new class of treatments, which include induced pluripotent stem cell (iPSC)-derived tissues that aim to replace degenerated cells. iPSCs can potentially be used to generate any cell type of the body, making them a powerful tool for treating degenerative diseases. Cell replacement for retinal degenerative diseases is at the forefront of cell therapies, given the accessibility of the eye for surgical procedures and a huge unmet medical need for retinal degenerative diseases with no current treatment options. Clinical trials are ongoing in different parts of the world using stem cell-derived retinal pigment epithelium (RPE). This review focuses on scientific and regulatory considerations when developing an iPSC-derived RPE cell therapy from the development of a robust and efficient differentiation protocol to critical quality control assays for cell validation, the choice of an appropriate animal model for preclinical testing, and the regulatory aspects that dictate the final approval for proceeding to a first-in-human clinical trial.

Rodent models of breast cancer have played critical roles in our understanding of breast cancer development and progression as well as preclinical testing of cancer prevention and therapeutics. In this article, we first review the values and challenges of conventional genetically engineered mouse (GEM) models and newer iterations of these models, especially those with inducible or conditional regulation of oncogenes and tumor suppressors. Then, we discuss nongermline (somatic) GEM models of breast cancer with temporospatial control, made possible by intraductal injection of viral vectors to deliver oncogenes or to manipulate the genome of mammary epithelial cells. Next, we introduce the latest development in precision editing of endogenous genes using in vivo CRISPR-Cas9 technology. We conclude with the recent development in generating somatic rat models for modeling estrogen receptor-positive breast cancer, something that has been difficult to accomplish in mice.

Human retinal organoids recapitulate the cellular diversity, arrangement, gene expression, and functional aspects of the human retina. Protocols to generate human retinal organoids from pluripotent stem cells are typically labor intensive, include many manual handling steps, and the organoids need to be maintained for several months until they mature. To generate large numbers of human retinal organoids for therapy development and screening purposes, scaling up retinal organoid production, maintenance, and analysis is of utmost importance. In this review, we discuss strategies to increase the number of high-quality retinal organoids while reducing manual handling steps. We further review different approaches to analyze thousands of retinal organoids with currently available technologies and point to challenges that still await to be overcome both in culture and analysis of retinal organoids.

Naturally occurring inherited retinal diseases (IRDs) in cats and dogs provide a rich source of potential models for human IRDs. In many cases, the phenotypes between the species with mutations of the homologous genes are very similar. Both cats and dogs have a high-acuity retinal region, the area centralis, an equivalent to the human macula, with tightly packed photoreceptors and higher cone density. This and the similarity in globe size to that of humans means these large animal models provide information not obtainable from rodent models. The established cat and dog models include those for Leber congenital amaurosis, retinitis pigmentosa (including recessive, dominant, and X-linked forms), achromatopsia, Best disease, congenital stationary night blindness and other synaptic dysfunctions, RDH5-associated retinopathy, and Stargardt disease. Several of these models have proven to be important in the development of translational therapies such as gene-augmentation therapies. Advances have been made in editing the canine genome, which necessitated overcoming challenges presented by the specifics of canine reproduction. Feline genome editing presents fewer challenges. We can anticipate the generation of specific cat and dog IRD models by genome editing in the future.

Our ability to interrogate the tumor immune microenvironment (TIME) at an ever-increasing granularity has uncovered critical determinants of disease progression. Not only do we now have a better understanding of the immune response in breast cancer, but it is becoming possible to leverage key mechanisms to effectively combat this disease. Almost every component of the immune system plays a role in enabling or inhibiting breast tumor growth. Building on early seminal work showing the involvement of T cells and macrophages in controlling breast cancer progression and metastasis, single-cell genomics and spatial proteomics approaches have recently expanded our view of the TIME. In this article, we provide a detailed description of the immune response against breast cancer and examine its heterogeneity in disease subtypes. We discuss preclinical models that enable dissecting the mechanisms responsible for tumor clearance or immune evasion and draw parallels and distinctions between human disease and murine counterparts. Last, as the cancer immunology field is moving toward the analysis of the TIME at the cellular and spatial levels, we highlight key studies that revealed previously unappreciated complexity in breast cancer using these technologies. Taken together, this article summarizes what is known in breast cancer immunology through the lens of translational research and identifies future directions to improve clinical outcomes.

Cellular senescence was initially described in the early 1960s by Hayflick and Moorehead. They noted sustained cell-cycle arrest after repeated subculturing of human primary cells. Over half a century later, cellular senescence has become recognized as one of the fundamental pillars of aging. Developing senotherapeutics, interventions that selectively eliminate or target senescent cells, has emerged as a key focus in health research. In this article, we note major milestones in cellular senescence research, discuss current challenges, and point to future directions for this rapidly growing field.