Kinase Inhibitors’ Effects on Innate Immunity in Solid Cancers

Innate immune cells constitute a plastic and heterogeneous cell population of the tumor microenvironment. Because of their high tumor infiltration and close interaction with resident tumor cells, they are compelling targets for anti-cancer therapy through either ablation or functionally reprogramming. Kinase inhibitors (KIs) that target aberrant signaling pathways in tumor proliferation and angiogenesis have been shown to have additional immunological effects on myeloid cells that may contribute to a protective antitumor immune response. However, in patients with malignancies, these effects are poorly described, warranting meticulous research to identify KIs’ optimal immunomodulatory effect to support developing targeted and more effective immunotherapy. As many of these KIs are currently in clinical trials awaiting approval for the treatment of several types of solid cancer, we evaluate here the information on this drug class’s immunological effects and how such mechanisms can be harnessed to improve combined treatment regimens in cancer.

Astrocytes in Multiple Sclerosis—Essential Constituents with Diverse Multifaceted Functions

In multiple sclerosis (MS), astrocytes respond to the inflammatory stimulation with an early robust process of morphological, transcriptional, biochemical, and functional remodeling. Recent studies utilizing novel technologies in samples from MS patients, and in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), exposed the detrimental and the beneficial, in part contradictory, functions of this heterogeneous cell population. In this review, we summarize the various roles of astrocytes in recruiting immune cells to lesion sites, engendering the inflammatory loop, and inflicting tissue damage. The roles of astrocytes in suppressing excessive inflammation and promoting neuroprotection and repair processes is also discussed. The pivotal roles played by astrocytes make them an attractive therapeutic target. Improved understanding of astrocyte function and diversity, and the mechanisms by which they are regulated may lead to the development of novel approaches to selectively block astrocytic detrimental responses and/or enhance their protective properties.

Kinetics of influenza A virus infections in a heterogeneous cell population

Kinetics of influenza A virus infections in a heterogeneous cell population

Kinetics of influenza A virus infections in a heterogeneous cell population

Kinetics of influenza A virus infections in a heterogeneous cell population

Nonclassical monocytes in cardiovascular physiology and disease

Monocytes are a heterogeneous cell population of innate immune cells with distinct cell surface markers that help them in carrying out different functions. In humans, there are three well-characterized subsets, namely, classical (CD14++CD16−), intermediate (CD14++CD16+), and nonclassical (CD14+ CD16++) monocytes. There is an emerging focus on the not yet well explored nonclassical monocytes that maintain vascular integrity by slowly patrolling on the endothelium, reacting to inflammatory signals, and clearing cell debris. In this manner, they are not only crucial for vascular homeostasis but also play a vital role in wound healing and resolution of inflammation by linking innate to adaptive immune response. Although they have been shown to be protective, yet they are also associated with inflammatory disease progression. This short review will give an insight about the emerging role of nonclassical monocytes in vascular homeostasis, inflammation, and protection in the context of cardiovascular disease.

Identification of functionally distinct macrophage subpopulations in Drosophila

Vertebrate macrophages are a highly heterogeneous cell population, but whileDrosophilablood is dominated by a macrophage-like lineage (plasmatocytes), until very recently these cells were considered to represent a homogeneous population. Here, we present our identification of enhancer elements labelling plasmatocyte subpopulations, which vary in abundance across development. These subpopulations exhibit functional differences compared to the overall population, including more potent injury responses and differential localisation and dynamics in pupae and adults. Our enhancer analysis identified candidate genes regulating plasmatocyte behaviour: pan-plasmatocyte expression of one such gene (Calnexin14D) improves wound responses, causing the overall population to resemble more closely the subpopulation marked by theCalnexin14D-associated enhancer. Finally, we show that exposure to increased levels of apoptotic cell death modulates subpopulation cell numbers. Taken together this demonstrates macrophage heterogeneity inDrosophila, identifies mechanisms involved in subpopulation specification and function and facilitates the use ofDrosophilato study macrophage heterogeneity in vivo.

Genetic targeting of neurogenic precursors in the adult forebrain ventricular epithelium

The ventricular epithelium of the adult forebrain is a heterogeneous cell population that is a source of both quiescent and activated neural stem cells (qNSCs and aNSCs, respectively). We genetically targeted a subset of ventricle-contacting, glial fibrillary acidic protein (GFAP)-expressing cells, to study their involvement in qNSC/aNSC–mediated adult neurogenesis. Ventricle-contacting GFAP+ cells were lineage-traced beginning in early adulthood using adult brain electroporation and produced small numbers of olfactory bulb neuroblasts until at least 21 mo of age. Notably, electroporated GFAP+ neurogenic precursors were distinct from both qNSCs and aNSCs: they did not give rise to neurosphere-forming aNSCs in vivo or after extended passaging in vitro and they were not recruited during niche regeneration. GFAP+ cells with these properties included a FoxJ1+GFAP+ subset, as they were also present in an inducible FoxJ1 transgenic lineage-tracing model. Transiently overexpressing Mash1 increased the neurogenic output of electroporated GFAP+ cells in vivo, identifying them as a potentially recruitable population. We propose that the qNSC/aNSC lineage of the adult forebrain coexists with a distinct, minimally expanding subset of GFAP+ neurogenic precursors.

Eph/ephrin Signaling and Biology of Mesenchymal Stromal/Stem Cells

Mesenchymal stromal/stem cells (MSCs) have emerged as important therapeutic agents, owing to their easy isolation and culture, and their remarkable immunomodulatory and anti-inflammatory properties. However, MSCs constitute a heterogeneous cell population which does not express specific cell markers and has important problems for in vivo homing, and factors regulating their survival, proliferation, and differentiation are largely unknown. Accordingly, in the present article, we review the current evidence on the relationships between Eph kinase receptors, their ephrin ligands, and MSCs. These molecules are involved in the adult homeostasis of numerous tissues, and we and other authors have demonstrated their expression in human and murine MSCs derived from both bone marrow and adipose tissue, as well as their involvement in the MSC biology. We extend these studies providing new results on the effects of Eph/ephrins in the differentiation and immunomodulatory properties of MSCs.

Time- and Kellgren–Lawrence Grade-Dependent Changes in Intra-Articularly Transplanted Stromal Vascular Fraction in Osteoarthritic Patients

Knee osteoarthritis (OA) is one of the most prevalent disorders in elderly population. Among various therapeutic alternatives, we employed stromal vascular fraction (SVF), a heterogeneous cell population, to regenerate damaged knee cartilage. OA patients were classified on the basis of age, gender, body mass index (BMI), and x-ray-derived Kellgren–Lawrence (KL) grade. They were treated with SVF and followed-up for 24 months. Visual analogue scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index were used to determine treatment efficacy. Cartilage healing was assessed using the MRI-based Outerbridge score (OS) and evaluation of bone marrow edema (BME) lesions, while a placebo group was used as a control. Time- and KL-dependent changes were also monitored. We observed a decreasing trend in VAS score and WOMAC index in the SVF-treated group up to 24 months, as compared with the placebo group. Besides, a significant increase and decrease in Lysholm and OS, respectively, were observed in the treatment group. Compared with the values before treatment, the greatly reduced WOMAC scores of KL3 than KL2 groups at 24 months, indicate more improvement in the KL3 group. Highly decreased BME in the treated group was also noted. In conclusion, the SVF therapy is effective in the recovery of OA patients of KL3 grade in 24 months.