Cell Types Research Articles

Precision Control of Cell Type-Specific Behavior via RNA Sensing and Editing.

In the realms of bioengineering and biopharmaceuticals, there exists a critical demand for advanced genetic tools that can interact with specific cell signaling pathways to accurately identify and target various cell types. This research introduces the innovative CRISPR-ADAReader system, which enables precise manipulation of cell activity through sensing target RNA. Featuring both positive and negative feedback loops, the system allows for tailored regulation across different cell types in response to various internal signals, showcasing exceptional programmability, specificity, and sensitivity. By choosing distinct RNAs as activation signals, the CRISPR-ADAReader efficiently monitors and alters targeted cell behaviors. In a case study focusing on retinoblastoma treatment, the system distinctively initiates positive feedback and self-silencing actions by detecting MCYN and Rb transcripts, thus safeguarding normal retinal pigment epithelial cells while promoting apoptosis in cancer cells. Moreover, the CRISPR-ADAReader demonstrates significant anti-tumor effectiveness in live models, markedly reducing retinoblastoma cell proliferation through the activation of several cancer-suppression pathways, outperforming the capabilities of the ADAR-sensor. Notably, the system also shows an excellent in vivo safety profile. In conclusion, the CRISPR-ADAReader system represents a groundbreaking method for the detection and editing of RNA, offering a potent instrument for the customized and precise governance of cell behavior.

Long Noncoding RNA Function in Smooth Muscle Cell Plasticity and Atherosclerosis.

In the healthy mature artery, vascular cells, including endothelial cells, smooth muscle cells (SMCs), and fibroblasts are organized in different layers, performing specific functions. SMCs located in the media are in a differentiated state and exhibit a contractile phenotype. However, in response to vascular injury within the intima, stimuli from activated endothelial cells and recruited inflammatory cells reach SMCs and induce a series of remodeling events in them, known as phenotypic switching. Indeed, SMCs retain a certain degree of plasticity and are able to transdifferentiate into other cell types that are crucial for both the formation and development of atherosclerotic lesions. Because of their highly cell-specific expression profiles and their widely recognized contribution to physiological and disease-related biological processes, long noncoding RNAs have received increasing attention in atherosclerosis research. Dynamic fluctuations in their expression have been implicated in the regulation of SMC identity. Sophisticated technologies are now available to allow researchers to access single-cell transcriptomes and study long noncoding RNA function with unprecedented precision. Here, we discuss the state of the art of long noncoding RNAs regulation of SMC phenotypic switching, describing the methodologies used to approach this issue and evaluating the therapeutic perspectives of exploiting long noncoding RNAs as targets in atherosclerosis.

Maintenance of Cardiac Microenvironmental Homeostasis: A Joint Battle of Multiple Cells.

Various cells such as cardiomyocytes, fibroblasts and endothelial cells constitute integral components of cardiac tissue. The health and stability of cardiac ecosystem are ensured by the action of a certain type of cell and the intricate interactions between multiple cell types. The dysfunctional cells exert a profound impact on the development of cardiovascular diseases by involving in the pathological process. In this paper, we introduce the dynamic activity, cell surface markers as well as biological function of the various cells in the heart. Besides, we discuss the multiple signaling pathways involved in the cardiac injury including Hippo/YAP, TGF-β/Smads, PI3K/Akt, and MAPK signaling. The complexity of different cell types poses a great challenge to the disease treatment. By characterizing the roles of various cell types in cardiovascular diseases, we sought to discuss the potential strategies for preventing and treating cardiovascular diseases.

Plant-derived EpCAM-Fc fusion proteins induce in vivo immune response to produce IgGs inhibiting invasion and migration of colorectal cancer cells.

Transgenic tobacco plant expressed EpCAM-Fc fusion proteins to induce in vivo immune responses producing anti-EpCAM antibodies inhibiting human colorectal cancer cell invasion and migration. Plant is emerging as a promising alternative to produce valuable immunotherapeutic vaccines. In this study, we examined the in vivo anti-cancer efficacy of epidermal cell adhesion molecule (EpCAM)-Fc and EpCAM-FcK fusion proteins produced in transgenic plants as colorectal cancer vaccine candidates. Mice were injected with plant-derived EpCAM-Fc (EpCAM-FcP) and EpCAM-FcP tagged with KDEL (ER retention signal) (EpCAM-FcKP), using mammalian-derived EpCAM-Fc (EpCAM-FcM) as positive control. Total IgGs from the immunized mice were used to assess immune responses. ELISA tests revealed that IgGs from mice immunized with EpCAM-FcKP (EpCAM-FcKP IgG) exhibited the highest absorbance value for binding affinity to recombinant EpCAM-FcM compared to IgGs from mice immunized with EpCAM-FcP (EpCAM-FcP IgG) and EpCAM-FcM (EpCAM-FcM IgG). Bio-layer interferometry revealed that EpCAM-FcKP IgG had a higher affinity value than EpCAM-FcM IgG and EpCAM-FcP IgG. Cell ELISA revealed that EpCAM-FcKP IgG exhibited the highest binding activity to EpCAM-positive cells SW480 and SW620 compared to EpCAM-FcP IgG, EpCAM-FcM IgG, and anti-EpCAM mAb. In the transwell invasion assay, EpCAM-FcKP IgG significantly decreased the numbers of invaded SW480 and SW620 cells compared to EpCAM-FcP IgG, whereas EpCAM-FcM IgG had similar numbers. In the wound healing assay, EpCAM-FcKP IgG showed higher migration inhibition compared to EpCAM-FcP IgG in both cell types, with similar results to EpCAM-FcM IgG in SW620 cells. These results confirm the applicability of plant systems to produce EpCAM-Fc vaccine candidates, inducing the production of anti-EpCAM IgGs against colorectal cancer cells.

Emerging role of exosomes during the pathogenesis of viral hepatitis, non-alcoholic steatohepatitis and alcoholic hepatitis.

Extracellular vesicles (EVs) refer to a diverse range of membranous vesicles that are secreted by various cell types, they can be categorized into two primary subgroups: exosomes and microvesicles. Specifically, exosomes constitute a nanosized subset of EVs characterized by their intact lipid bilayer and diameters ranging from 30 to 150nm. These vesicles play a crucial role in intercellular communication by transporting a diverse array of biomolecules, which act as cargoes for this communication process. Exosomes have demonstrated significant implications in a wide range of biologic processes and pathologic conditions, including immunity, development, cancer, neurodegenerative diseases, and liver diseases. Liver diseases significantly contribute to the global burden of morbidity and mortality, yet their pathogenesis remains complex and effective therapies are relatively scarce. Emerging evidence suggests that exosomes play a modulatory role in the pathogenesis of liver diseases, including viral hepatitis, non-alcoholic steatohepatitis (NASH), and alcoholic hepatitis (AH). These findings bolster our confidence in the potential of exosomes as biomarkers and therapeutic tools for the diagnosis and treatment of liver diseases. In this comprehensive review, we offer a straightforward overview of exosomes and summarize the current understanding of their role in the pathogenesis of liver diseases. This provides a foundation for novel diagnostic and therapeutic approaches in the treatment of liver diseases.

Identification of rare disease genes as drivers of common diseases through tissue-specific gene regulatory networks

Genetic variants identified through genome-wide association studies (GWAS) are typically non-coding, exerting small regulatory effects on downstream genes. However, which downstream genes are ultimately impacted and how they confer risk remains mostly unclear. By contrast, variants that cause rare Mendelian diseases are often coding and have a more direct impact on disease development. Here we demonstrate that common and rare genetic diseases can be linked by studying how common disease-associated variants influence gene co-expression in 57 different tissues and cell types. We implemented this method in a framework called Downstreamer and applied it to 88 GWAS traits. We find that predicted downstream “genes” are enriched with Mendelian disease genes, e.g. key genes for height are enriched for genes that cause skeletal abnormalities and Ehlers–Danlos syndromes. 78% of these key genes are located outside of GWAS loci, suggesting that they result from complex trans regulation rather than being impacted by disease-associated variants in cis. Based on our findings, we discuss the challenges in reconstructing gene regulatory networks and provide a roadmap to improve the identification of these highly connected genes linked to common traits and diseases.

Comparison of C-type Nanoantibody Produced in Different Expression Systems Implying Potential Clinical Applications.

In the pharmaceutical industry, the Chinese hamster ovary cell, a type of mammalian cell, is extensively employed for the production of conventional full-length monoclonal antibodies. Nanobody is one of the most attractive directions for the development of next-generation antibody drugs. However, a suitable expression system for its manufacture has not yet been comprehensively evaluated. Previously, we proposed that the immunoglobulin constant CH2 domain could be a promising scaffold for developing C-type nanoantibodies (C-Nabs) as candidate therapeutics. Here, we used an antiviral C-Nab, which we identified previously (under review), as a model for investigation. We expressed C-Nabs without a tag in different systems, including a bacterium (C-Nabbac), yeast (C-Nabyeast), and mammalian cell (C-Nabmam). After purification, the binding and neutralizing activities of C-Nabs from different expression systems are similar. Their secondary structures are rich in β-strand. The melting temperatures of C-Nabbac (71.5 °C) and C-Nabmam (70.2 °C) are similar, which are slightly higher than that of C-Nabyeast (65.6 °C), while C-Nabyeast and C-Nabmam are more resistant to urea-induced unfolding than C-Nabbac. C-Nabyeast and C-Nabmam demonstrate higher resistance to aggregation compared to C-Nabbac. C-Nabyeast exhibits greater resistance to enzyme digestion compared to C-Nabbac and C-Nabmam. Notably, when administered via intraperitoneal injection in mice, C-Nabyeast shows superior pharmacokinetics. Overall, after comparing C-Nab proteins from various expression systems, we determined that yeast is the most suitable host for producing C-Nabs. This finding is beneficial for the production of nanobodies as potential drug candidates.

Machine learning-based analysis of programmed cell death types and key genes in intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is intricately associated with various forms of programmed cell death (PCD). Identifying key PCD types and associated genes is essential for understanding the molecular mechanisms underlying IVDD and discovering potential therapeutic targets. This study aimed to elucidate core PCD types, related genes, and potential drug interactions in IVDD using comprehensive bioinformatic and experimental approaches. Using datasets GSE167199, GSE176205, GSE34095, GSE56081, and GSE70362, relevant gene expression and clinical data were analyzed. Differential expression gene (DEG) analysis identified upregulated genes linked to 15 PCD types. Gene Set Variation Analysis (GSVA) was employed to pinpoint key PCD types contributing to disc degeneration. Core genes were identified through machine learning techniques, while immune infiltration and single-cell analysis helped identify apoptosis-related cell types. Molecular docking, along with in vivo and in vitro experiments using a murine IVDD model, validated potential drug interactions. The results identified apoptosis, autophagy, ferroptosis, and necroptosis as key PCD types in IVDD. A gene module associated with apoptosis showed a strong correlation with the severity of disc degeneration, revealing 34 central genes in the gene network. Drug screening identified Glibenclamide as effectively interacting with PDCD6 and UBE2K. Subsequent in vitro and in vivo experiments demonstrated that Glibenclamide reduced apoptosis and delayed disc degeneration progression. This study provides a comprehensive bioinformatics analysis of PCD in IVDD, identifying four primary PCD types contributing to the disease's progression. The findings offer novel insights into the molecular pathology of disc degeneration and suggest promising therapeutic strategies for future treatment development.

Stimulation of locus coeruleus inputs to the prelimbic cortex in mice induces cell type-specific expression of the Apoe gene.

The medial frontal cortex (mFC) and locus coeruleus (LC) are two brain areas that have been implicated in a range of cognitive phenomena, such as attention, memory, and decision making. Regulators of these brain regions at the molecular level are not well understood, but might help to elucidate underlying mechanisms of disorders that present with deficits in these cognitive domains. To probe this, we used chemogenetic stimulation of neurons in the LC with axonal projections to the prelimbic subregion (PrL) of the mFC, and subsequent bulk RNA-sequencing from the mouse PrL. We found that stimulation of this circuit caused an increase in transcription of a host of genes, including the Apoe gene. To investigate cell type-specific expression of Apoe in the PrL, we used a dual-virus approach to express either the excitatory DREADD receptor hM3Dq in LC neurons with projections to the PrL, or a control virus, and found that increases in Apoe expression in the PrL following depolarization of LC inputs is enriched in GABAergic neurons in a sex-dependent manner. The results of these experiments yield insights into how Apoe expression affects function in a cortical microcircuit that is important for attention, memory, and decision making, and point to interneuron-specific expression of Apoe as a potential biomarker for circuit function in disorders such as attention-deficit hyperactivity disorder (ADHD), schizophrenia, and Alzheimer's disease (AD).Significance Statement Identifying patterns of gene expression in specific brain circuits is an important first step toward developing treatments for cognitive and behavioral symptoms that rely on those circuits. In this paper, we describe a transcriptome-scale motif in one such circuit - neurons in the LC that project to the PrL. This circuit has been implicated in attention, memory, and decision making, and deficits in these cognitive domains are common across many neuropsychiatric disorders. We further explored one of the top differentially expressed genes, Apoe, to identify how it is expressed in distinct cell types following stimulation of this circuit, paving the way for spatially- and genetically-specific targeting of this gene in disorders that feature dysfunction in this circuit.

Complete Genomic Landscape Reveals Hidden Evolutionary History and Selection Signature in Asian Water Buffaloes (Bubalus bubalis).

To identify the genetic determinants of domestication and productivity of Asian water buffaloes (Bubalus bubalis), 470 genomes of domesticated river and swamp buffaloes along with their putative ancestors, the wild water buffaloes (Bubalus arnee) are sequenced and integrated. The swamp buffaloes inherit the morphology of the wild buffaloes. In contrast, most river buffaloes are unique in their morphology, but their genomes cluster with the wild buffaloes. The levels of genomic diversity in Italian river and Indonesian swamp buffaloes decrease at opposite extremes of their distribution range. Purifying selection prevented the accumulation of harmful loss-of-function variants in the Indonesian buffaloes. Genes that evolved rapidly (e.g., GKAP1) following differential selections in the river and swamp buffaloes are involved in their reproduction. Genes related to milk production (e.g., CSN2) and coat color (e.g., MC1R) underwent strong selections in the dairy river buffaloes via soft and hard selective sweeps, respectively. The selective sweeps and single-cell RNA-seq data revealed the luminal cells as the key cell type in response to artificial selection for milk production of the dairy buffaloes. These findings show how artificial selection has been driving the evolutionary divergence and genetic differentiation in morphology and productivity of Asian water buffaloes.

Spatial Transcriptome and Single Nucleus Transcriptome Sequencing Reveals Tetrahydroxy Stilbene Glucoside Promotes Ovarian Organoids Development Through the Vegfa-Ephb2 Pair.

Ovarian dysfunction is a major factor leading to female infertility. Understanding how to improve or reshape ovarian function has become an important entry point for preventing and treating female infertility caused by ovarian dysfunction. Here, plant-derived compounds are screened for in vitro activity upon ovarian organoids derived from feeder-free female germline stem cells. Tetrahydroxy stilbene glucoside (TSG) is found to promote the development of ovarian organoids. Single nucleus transcriptome sequencing and spatial transcriptome sequencing are used to establish a comprehensive spatiotemporal map to elucidate the role of TSG in ovarian organoid development, encompassing cell types and subtypes, transcription factors, pseudo-time sequence, and cell communication dynamics. This analysis indicates that TSG promotes ovarian organoid development through the vascular endothelial growth factor A-Eph receptor B2 ligand-receptor pair between granulosa cells and oocytes. This study has enhanced the understanding of the mechanisms of ovarian organoid development, establishes a technical platform for screening compounds for treating infertility and related diseases, and lays a foundation for clinically applying plant-derived compounds.

Genetic control of alternative splicing across blood cell types from diverse Asian donors.

Genetic control of alternative splicing across blood cell types from diverse Asian donors.

The X-linked intellectual disability gene CUL4B is critical for memory and synaptic function

Cullin 4B (CUL4B) is the scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Loss-of-function mutations in the human CUL4B gene lead to syndromic X-linked intellectual disability (XLID). Till now, the mechanism of intellectual disability caused by CUL4B mutation still needs to be elucidated. In this study, we used single-nucleus RNA sequencing (snRNA-seq) to investigate the impact of CUL4B deficiency on the transcriptional programs of diverse cell types. The results revealed that depletion of CUL4B resulted in impaired intercellular communication and elicited cell type-specific transcriptional changes relevant to synapse dysfunction. Golgi-Cox staining of brain slices and immunostaining of in vitro cultured neurons revealed remarkable synapse loss in CUL4B-deficient mice. Ultrastructural analysis via transmission electron microscopy (TEM) showed that the width of the synaptic cleft was significantly greater in CUL4B-deficient mice. Electrophysiological experiments found a decrease in the amplitude of AMPA receptor-mediated EPSCs in the hippocampal CA1 pyramidal neurons of CUL4B-deficient mice. These results indicate that depletion of CUL4B in mice results in morphological and functional abnormalities in synapses. Furthermore, behavioral tests revealed that depletion of CUL4B in the mouse nervous system results in impaired spatial learning and memory. Taken together, the findings of this study reveal the pathogenesis of neurological disorders associated with CUL4B mutations and promote the identification of therapeutic targets that can halt synaptic abnormalities and preserve memory in individuals.

Advanced MicroRNA delivery for lung inflammatory therapy: surfactant protein A controls cellular internalisation and degradation of extracellular vesicles

IntroductionAlveolar macrophages (AMs) are the first line of defence against pathogens that initiate an inflammatory response in the lungs and exhibit a strong affinity for surfactant protein A (SP-A). Extracellular...

BRAFV600E induces key features of LCH in iPSCs with cell type-specific phenotypes and drug responses.

Langerhans cell histiocytosis (LCH) is a clonal hematopoietic disorder defined by tumorous lesions containing CD1a+/CD207+ cells. Two severe complications of LCH are systemic hyperinflammation and progressive neurodegeneration. The scarcity of primary samples and lack of appropriate models limit our mechanistic understanding of LCH pathogenesis and affect patient care. We generated a human in vitro model for LCH using induced pluripotent stem cells (iPSCs) harboring the BRAFV600E mutation, the most common genetic driver of LCH. We show that BRAFV600E/WT iPSCs display myelo-monocytic skewing during hematopoiesis and spontaneously differentiate into CD1a+/CD207+ cells that are similar to lesional LCH cells and are derived from a CD14+ progenitor. We show that BRAFV600E modulates the expression of key transcription factors regulating monocytic differentiation and leads to an upregulation of pro-inflammatory molecules and LCH marker genes early during myeloid differentiation. In vitro drug testing revealed that BRAFV600E-induced transcriptomic changes are reverted upon treatment with MAPK-pathway inhibitors (MAPKi). Importantly, MAPKi do not affect myeloid progenitors but reduces only the mature CD14+ cell population. Furthermore, iPSC-derived neurons (iNeurons) co-cultured with BRAFV600E/WT iPSC-derived microglia-like cells (iMGL), differentiated from iPSC-derived CD34+ progenitors, exhibit signs of neurodegeneration with neuronal damage and release of neurofilament light chain. In summary, the iPSC-based model described here provides a platform to investigate the effects of BRAFV600E in different hematopoietic cell types and provides a tool to compare and identify novel approaches for the treatment of BRAFV600E-driven diseases.

ELemur: A cellular-resolution 3D atlas of the mouse lemur brain

The gray mouse lemur (Microcebus murinus), one of the smallest living primates, emerges as a promising model organism for neuroscience research. This is due to its genetic similarity to humans, its evolutionary position between rodents and humans, and its primate-like features encapsulated within a rodent-sized brain. Despite its potential, the absence of a comprehensive reference brain atlas impedes the progress of research endeavors in this species, particularly at the microscopic level. Existing references have largely been confined to the macroscopic scale, lacking detailed anatomical information. Here, we present eLemur, a unique resource, comprising a repository of high-resolution brain-wide images immunostained with multiple cell type and structural markers, elucidating the cyto- and chemoarchitecture of the mouse lemur brain. Additionally, it encompasses a segmented two-dimensional reference and 3D anatomical brain atlas delineated into cortical, subcortical, and other vital regions. Furthermore, eLemur includes a comprehensive 3D cell atlas, providing densities and spatial distributions of non-neuronal and neuronal cells across the mouse lemur brain. Accessible via a web-based viewer (https://eeum-brain.com/#/lemurdatasets), the eLemur resource streamlines data sharing and integration, fostering the exploration of different hypotheses and experimental designs using the mouse lemur as a model organism. Moreover, in conjunction with the growing 3D datasets for rodents, nonhuman primates, and humans, our eLemur 3D digital framework enhances the potential for comparative analysis and translation research, facilitating the integration of extensive rodent study data into human studies.

Identification of SPP1+ macrophages as an immune suppressor in hepatocellular carcinoma using single-cell and bulk transcriptomics

IntroductionMacrophages and T cells play crucial roles in liver physiology, but their functional diversity in hepatocellular carcinoma (HCC) remains largely unknown.MethodsTwo bulk RNA-sequencing (RNA-seq) cohorts for HCC were analyzed using gene co-expression network analysis. Key gene modules and networks were mapped to single-cell RNA-sequencing (scRNA-seq) data of HCC. Cell type fraction of bulk RNA-seq data was estimated by deconvolution approach using single-cell RNA-sequencing data as a reference. Survival analysis was carried out to estimate the prognosis of different immune cell types in bulk RNA-seq cohorts. Cell-cell interaction analysis was performed to identify potential links between immune cell types in HCC.ResultsIn this study, we analyzed RNA-seq data from two large-scale HCC cohorts, revealing a major and consensus gene co-expression cluster with significant implications for immunosuppression. Notably, these genes exhibited higher enrichment in liver macrophages than T cells, as confirmed by scRNA-seq data from HCC patients. Integrative analysis of bulk and single-cell RNA-seq data pinpointed SPP1+ macrophages as an unfavorable cell type, while VCAN+ macrophages, C1QA+ macrophages, and CD8+ T cells were associated with a more favorable prognosis for HCC patients. Subsequent scRNA-seq investigations and in vitro experiments elucidated that SPP1, predominantly secreted by SPP1+ macrophages, inhibits CD8+ T cell proliferation. Finally, targeting SPP1 in tumor-associated macrophages through inhibition led to a shift towards a favorable phenotype.DiscussionThis study underpins the potential of SPP1 as a translational target in immunotherapy for HCC.

Epigenetic regulation of complement C1Q gene expression

Human C1q is a multifaceted complement protein whose functions range from activating the complement classical pathway to immunomodulation and promoting placental development and tumorigenesis. It is encoded by the C1QA, C1QB, and C1QC genes located on chromosome 1. C1q, unlike most complement components, has extrahepatic expression by a range of cells including macrophages, monocytes and immature dendritic cells. Its local synthesis under the conditions of inflammation and for the purpose of removal of altered self requires its strict transcriptional regulation. To delve into C1Q transcriptional regulation and unravel potential epigenetic influences, we conducted an in silico analysis utilizing a range of online tools and datasets. Co-expression analysis revealed tight coordination between C1QA, C1QB, and C1QC genes. Strikingly, distinct epigenetic patterns emerged across various cell types expressing or lacking these genes, with unique histone marks and DNA methylation status characterizing their regulatory landscape. Notably, the investigation extended to tumor contexts, unveiled potential epigenetic roles in malignancies. The cell type and tumor-specific histone modifications and chromatin accessibility patterns underscore the dynamic nature of epigenetic regulation of C1Q, providing crucial insights into the intricate mechanisms governing the expression of these immunologically significant genes. The findings provide a foundation for future investigations into targeted epigenetic modulation, offering insights into potential therapeutic avenues for immune-related disorders and cancer mediated via C1q.

Fibroblast Heterogeneity in Inflammatory Bowel Disease

Intestinal fibroblasts are pivotal players in maintaining tissue homeostasis and orchestrating responses to injury and inflammation within the gastrointestinal (GI) tract. Fibroblasts contribute significantly to the pathogenesis of inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis (UC), by secreting pro-inflammatory cytokines, modulating immune cell activity, and promoting fibrosis. In addition, fibroblasts play crucial roles in tissue repair and regeneration following acute injury or chronic inflammation. The dysregulation of fibroblast functions can lead to fibrotic complications, such as intestinal strictures and obstruction, which are common in advanced stages of IBD. Understanding the complex interplay between fibroblasts and other cell types in the intestine is essential to elucidate the underlying mechanisms of intestinal diseases and identify novel therapeutic targets. Future research aimed at deciphering the heterogeneity of intestinal fibroblasts and their dynamic roles in disease progression holds promise for the development of precision therapies to mitigate fibrosis and inflammation in intestinal disorders.

In Vivo Cardiovascular Molecular Imaging: Contributions to Precision Medicine and Drug Development

Conventional forms of noninvasive cardiovascular imaging that evaluate morphology, function, flow, and metabolism play a vital role in individual treatment decisions, often based on guidelines. Innovations in molecular imaging have enhanced our ability to spatially quantify the expression of a wider array of disease-related proteins, genes, or cell types, or the activity of specific pathogenic pathways. These techniques, which usually rely on design of targeted imaging probes, have already been used extensively in cancer medicine and have now become part of cardiovascular care in conditions such as amyloidosis and sarcoidosis. The recognition that common cardiovascular conditions are caused by a substantial diversity of pathobiologic pathways and the diversity of therapies available for use have rekindled interest in expanding the role of molecular imaging of tissue phenotype to improve precision in diagnosis and therapeutic decision-making. The intent of this article is to raise awareness and understanding of approaches to molecular or cellular imaging of phenotype with targeted probes, and their potential to promote the principles of precision medicine. Also addressed are the diverse roles of molecular imaging to improve precision and efficiency of new drug development at the stages of candidate identification, preclinical testing, and clinical trials.