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Summary: PDGFRα+ mesenchymal progenitor cells are associated with pathological fibro-adipogenic processes. Conversely, a beneficial role for these cells during homeostasis or in response to revascularization and regeneration stimuli is suggested, but remains to be defined. We studied the molecular profile and function of PDGFRα+ cells in order to understand the mechanisms underlying their role in fibrosis versus regeneration. We show that PDGFRα+ cells are essential for tissue revascularization and restructuring through injury-stimulated remodeling of stromal and vascular components, context-dependent clonal expansion, and ultimate removal of pro-fibrotic PDGFRα+-derived cells. Tissue ischemia modulates the PDGFRα+ phenotype toward cells capable of remodeling the extracellular matrix and inducing cell-cell and cell-matrix adhesion, likely favoring tissue repair. Conversely, pathological healing occurs if PDGFRα+-derived cells persist as terminally differentiated mesenchymal cells. These studies support a context-dependent “yin-yang” biology of tissue-resident mesenchymal progenitor cells, which possess an innate ability to limit injury expansion while also promoting fibrosis in an unfavorable environment. : Santini et al. show that progenitor PDGFRα+ cells residing in skeletal muscle are mesenchymal stromal cells with a dual function, which on the one hand can stabilize newly formed blood vessels and limit injury expansion after ischemia, but on the other hand are also capable of promoting fibrosis in an unfavorable environment. Keywords: platelet-derived growth factor receptor α, revascularization, regeneration, fibrosis, hindlimb ischemia, RNA sequencing, Brainbow

Summary Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor. To overlay this microenvironmental information with drug response, we applied a FRET biosensor for Akt activity, which is a key effector of the PI3K pathway. Performing dual intravital imaging of drug response in different tumor compartments, we demonstrate an improved drug response to a combination therapy using the dual mTORC1/2 inhibitor AZD2014 with the hypoxia-activated pro-drug TH-302., Graphical Abstract, Highlights • Hypoxia presents a moving pocket of resistance in pancreatic ductal adenocarcinoma. • Dual intravital imaging allows live tracking of drug response in hypoxic regions. • Combination with a hypoxia-activated pro-drug alleviates resistance. • This has implications for combatting resistance in a broad range of therapies., Intravital imaging facilitates the real-time tracking and targeting of moving hypoxic regions within pancreatic ductal adenocarcinoma. Using this approach, Conway et al. alleviate hypoxia-induced resistance to a dual mTORC1/2 inhibitor AZD2014, improving PI3K pathway inhibition and demonstrating a powerful dual imaging modality applicable to targeting other pathways and cancers.

The complex genetic origins of many human disorders suggest that epistatic (gene × gene) interactions may contribute to a significant proportion of their heritability estimates and phenotypic heterogeneity. Simultaneous disruption of the developmental genes and schizophrenia risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) in mice has been shown to produce disease-relevant and domain-specific phenotypic profiles different from that observed following disruption of either gene alone. In the current study, anxiety and stress responsivity phenotypes in male and female mutant mice with simultaneous disruption of DISC1 and NRG1 were examined. NRG1 × DISC1 mutant mice were generated and adult mice from each genotype were assessed for pain sensitivity (hot plate and tail flick tests), anxiety (light-dark box), and stress-induced hypothermia. Serum samples were assayed to measure circulating levels of pro-inflammatory cytokines. Mice with the NRG1 mutation, irrespective of DISC1 mutation, spent significantly more time in the light chamber, displayed increased core body temperature following acute stress, and decreased pain sensitivity. Basal serum levels of cytokines IL8, IL1β and IL10 were decreased in NRG1 mutants. Mutation of DISC1, in the absence of epistatic interaction with NRG1, was associated with increased serum levels of IL1β. Epistatic effects were evident for IL6, IL12 and TNFα. NRG1 mutation alters stress and pain responsivity, anxiety, and is associated with changes in basal cytokine levels. Epistasis resulting from synergistic NRG1 and DISC1 gene mutations altered pro-inflammatory cytokine levels relative to the effects of each of these genes individually, highlighting the importance of epistatic mechanisms in immune-related pathology.

Publisher Summary This chapter summarizes multiple functions of the best-characterized NK-2 class homeodomain proteins, Nkx2–5 and tin, during heart development, and the molecular mechanisms through which they execute their functions. NK-2 homeobox genes are essential for cardiogenesis in a wide range of species, reflecting the early deployment of these genes during the evolution of cardiac structures. As the complexity of the heart has increased during evolution, NK-2 genes have been utilized to control different processes. In vertebrates, Nkx2–5 represents a critical node in the complex transcriptional network governing the early specification and proliferation of the cardiac lineage in both the first and second heart fields of vertebrates, and during the subsequent molding of these progenitor cells into the mature organ. As outlined in this chapter, Nkx2–5 plays a role in almost all facets of heart development, including the regulation of cardiac progenitor cell number, the formation and patterning of the cardiac conduction system, septation, valve development, patterning of the venous returns, and the myogenic program. Importantly, Nkx2–5 does not act alone, but in concert with other highly-conserved transcription factors and signaling cascades to regulate cardiogenesis. Genome-wide expression profiling has begun to reveal Nkx2–5-dependent genes, and establishing which of these genes are direct targets remains the next challenge.

Inhalation is a prominent pathway for radiation dose contributions from environmental or occupational intakes of radioactive iodine. Radioactive iodine releases to the environment that affect the general public and deliver radiation dose are of particular concern. Inhalation intakes of iodine are possible from workplace exposures or releases to the environment, and potential health risks are an outcome. Extrathoracic and bronchial depositions follow a normal distribution. Bronchiolar and alveolar deposition are best fit by a lognormal distribution. Breathing rate, trachea diameter and particle mass density have the greatest influence on particulate deposition for 1 μm AMAD particles. In the United States, ICRP 30 is the lung model of regulatory concern and, therefore, the more commonly employed. The International Commission on Radiological Protection developed and issued the “New Lung Model” (ICRP, 66) in 1994. ICRP 66 incorporates recent knowledge and research into lung deposition, retention and clearance. Inhalation models are necessary for estimates of iodine uptake and deposition that may result in radiation exposure among workers or members of the public. The estimates of radiation dose via internal modeling have significant uncertainty, due to the variability in parameters involved in model calculations. The uncertainty in internal dosimetry can be a considerable component of the overall uncertainty in radiation dose assessment. The parameters used for dose assessment have inherent variability, which results in uncertainty for output variables that may be characterized by various known distributions.

This chapter reviews the origins and fate of myocardial progenitor cells throughout a series of events that define the embryonic heart tube and four-chambered heart. In addition, the molecular identity of conserved signaling molecules and transcription factors that drive early cardiomyogenesis and patterning and growth of the myocardium are discussed. Although the focus of this review is the embryologic origins of cardiomyocytes and their precursor cells in mammals, data from other vertebrate models are discussed where relevant to conserved mechanisms. Integration of both positive and negative signals from tissues surrounding the cardiogenic mesoderm results in progressive commitment toward a muscle fate. Differentiation occurs in a number of distinct directions that reflect the functional specificities of the chambers and other elements of the heart, and a process of de novo myogenesis contributes to muscularization of the intracardiac septa and valves. Whereas, the initial stages of heart tube formation are accompanied by continuing allocation of cardiomyocytes at the borders of cardiac epithelium, heart growth throughout fetal stages is driven largely by cardiomyocyte proliferation. Cardiomyocytes lose their proliferative capacity around birth and growth, and adaptation of the myocardium thereafter occurs largely through cellular hypertrophy in the presence of considerable endoreduplication but absence of cell division. Myocardial differentiation of mesodermal progenitor cells is a continuous process that initiates in the precardiac mesoderm and continues until the end of cardiac looping. After the completion of cardiac looping, the heart tube no longer grows by incorporation and differentiation of progenitor cells at the poles, but by proliferation of already existing cardiomyocytes within the embryonic heart.

This chapter discusses the molecular determinants of cardiac development and congential disease. The development of the mammalian heart is an exquisite example of how form is established during organ ontogeny and how relationships between form and function are realized. Although heart development has been studied at the morphological level since antiquity, its patterning principles are still far from clear. The details of the genes that guide heart myogenesis and morphogenesis are emerging at a rapid rate, contributing clues to patterning events and substantially informing the understanding of congenital, acquired, and maladaptive cardiac diseases. This chapter outlines recent progress on dissecting the molecular programs that guide heart formation and morphogenesis with emphasis on cardiac induction and the emergence of pattern through cellular and molecular interactions within the heart field and early heart tube. The information provides an essential framework that will allow genetic programs to be meaningfully linked to the emergence of heart form and function, and to the interpretation and amelioration of congenital heart disease.

Publisher Summary This chapter summarizes what is known about one specific gene family acting in transcriptional control and pattern formation in vertebrate and invertebrate hearts: the NK-2 class of homeodomain factors. It is found that frog Nkx2.5 is expressed in a region much broader than that occupied by the definitive heart progenitors, in a pattern resembling that of the morphogenetic field mapped in other amphibia. Thus, the regulatory ability of the field may be limited to the zone of Nkx2.5 expression. On the other hand, loss of regulatory ability in the field occurs in advance of the loss of the Nkx2.5 expression. In the fish, two NK-2 genes—nkx2.5 and nkx2. 7—are expressed in different but overlapping domains in a region encompassing the heart field. nkx2.5 expression occurs in those cells definitively fated to the heart but also extends more caudally beyond the heart field into cells that will never participate in heart development, even if definitive progenitors are killed by laser ablation. The notochord may provide inhibitory signals, which keep cells in the caudal region from differentiating as heart. Cells that participate in regulation have been mapped to the cranial region of the heart field, and these cells express nkx2.7 but not nkx2.5. The findings are consistent with the view that heart potency in the morphogenetic field requires the presence of a cardiac Nkx2 gene, but that other positive and negative interactions determine the actual extent of the definitive progenitors and of the field itself. Ectopic expression of Nkx2.5 in frog and fish embryos, achieved by microinjection of Nkx2.5 mRNA into fertilized eggs, leads to larger hearts and myocardial hyperplasia, without ectopic activation of the myogenic program.