Sars-CoV-2 Infection Prompts IL-1β-Mediated Inflammation and Reduces IFN-λ Expression in Human Lung Tissue

Two years after its spreading, the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) is still responsible for more than 2000 deaths per day worldwide, despite vaccines and monoclonal antibody countermeasures. Therefore, there is a need to understand the immune–inflammatory pathways that prompt the manifestation of the disease to identify a novel potential target for pharmacological intervention. In this context, the characterization of the main players in the SARS-CoV-2-induced cytokine storm is mandatory. To date, the most characterized have been IL-6 and the class I and II interferons, while less is known about the proinflammatory cytokine IL-1β and class III interferons. Here, we report a preliminary study aimed at the characterization of the lung inflammatory context in COVID-19 patients, with a special focus on IFN-λ and IL-1β. By investigating IFN and inflammatory cytokine patterns by IHC in 10 deceased patients due to COVID-19 infection, compared to 10 control subjects, we reveal that while IFN-β production was increased in COVID-19 patients, IFN-λ was almost abolished. At the same time, the levels of IL-1β were dramatically improved, while IL-6 lung levels seem to be unaffected by the infection. Our findings highlight a central role of IL-1β in prompting lung inflammation after SARS-CoV-2 infection. Together, we show that IFN-λ is negatively affected by viral infection, supporting the idea that IFN-λ administration together with the pharmaceutical blockage of IL-1β represents a promising approach to revert the COVID-19-induced cytokine storm

Mesenchymal stem cells: from the perivascular environment to clinical applications

Adult stem cells represent a fundamental biological system that has fascinated scientists over the last decades, and are currently the subject of a large number of studies aimed at better defining the properties of these cells, with a prominent focus on improving their application in regenerative medicine. One of the most used adult stem cells in clinical trials are mesenchymal stem cells (MSCs), which are multipotent cells able to differentiate into mature cells of mesodermal lineages. Following the initial studies on MSCs isolated from bone marrow, similar cells were also isolated from a variety of fetal and adult human tissues. Initially considered as identical and equipotent, MSCs from tissues other than bone marrow actually display differences in terms of their plastic abilities, which can be ascribed to the tissue of origin and/or to the procedures used for their isolation. Moreover, results from additional studies suggest that cultured MSCs represent the in vitro version of a subset of in vivo resident cells localized in the perivascular environment. In this review, we will focus our attention on MSCs from tissues other than bone marrow, their in vivo localization and their current applications in clinics

Not all pericytes are born equal: Pericytes from human adult tissues present different differentiation properties

Pericytes (PCs) have been recognized for a long time only as structural cells of the blood vessels. The identification of tight contacts with endothelial cells and the ability to interact with surrounding cells through paracrine signaling revealed additional functions of PCs in maintaining the homeostasis of the perivascular environment. PCs got the front page, in the late 1990s, after the identification and characterization of a new embryonic cell population, the mesoangioblasts, from which PCs present in the adult organism are thought to derive. From these studies, it was clear that PCs were also endowed with multipotent mesodermal abilities. Furthermore, their ability to cross the vascular wall and to reconstitute skeletal muscle tissue after systemic injection opened the way to a number of studies aimed to develop therapeutic protocols for a cell therapy of muscular dystrophy. This has resulted in a major effort to characterize pericytic cell populations from skeletal muscle and other adult tissues. Additional studies also addressed their relationship with other cells of the perivascular compartment and with mesenchymal stem cells. These data have provided initial evidence that PCs from different adult tissues might be endowed with distinctive differentiation abilities. This would suggest that the multipotent mesenchymal ability of PCs might be restrained within different tissues, likely depending on the specific cell renewal and repair requirements of each tissue. This review presents current knowledge on human PCs and highlights recent data on the differentiation properties of PCs isolated from different adult tissues

The Role of Mitochondria in Inflammation: From Cancer to Neurodegenerative Disorders

The main features that are commonly attributed to mitochondria consist of the regulation of cell proliferation, ATP generation, cell death and metabolism. However, recent scientific advances reveal that the intrinsic dynamicity of the mitochondrial compartment also plays a central role in proinflammatory signaling, identifying these organelles as a central platform for the control of innate immunity and the inflammatory response. Thus, mitochondrial dysfunctions have been related to severe chronic inflammatory disorders. Strategies aimed at reestablishing normal mitochondrial physiology could represent both preventive and therapeutic interventions for various pathologies related to exacerbated inflammation. Here, we explore the current understanding of the intricate interplay between mitochondria and the innate immune response in specific inflammatory diseases, such as neurological disorders and cancer

Human pericytes isolated from adipose tissue have better differentiation abilities than their mesenchymal stem cell counterparts

Multi-potent mesenchymal stem/progenitor cells are present in almost all organs and tissues, although their identity remains elusive. Several isolation strategies have been pursued to identify these cells prospectively, leading to the isolation of various cell populations endowed with multi-lineage mesodermal potential. Historically, mesenchymal stem cells (MSCs) were the first cell population to be isolated from the stromal fraction of most connective tissues. These cells are able to differentiate towards various mesodermal lineages and are currently the most studied adult mesodermal progenitors. Recently, the isolation of a subpopulation of microvascular pericytes (PCs) endowed with multi-lineage mesodermal potential has led to the identification of mesenchymal progenitors that reside in a defined anatomical location, namely the wall of small blood vessels. To gain insight into these two related cell populations, we performed a detailed analysis of the mesodermal potential of isogenic human MSCs and PCs isolated from white adipose tissue. Although both cell populations expressed known mesodermal markers at similar levels and displayed a comparable growth rate, PCs differentiated towards osteocytes, adipocytes and myocytes more efficiently than their MSC counterparts, as revealed by both histological and molecular assays. Our results show that microvascular PCs are more prone to mesenchymal differentiation than MSCs and therefore represent a preferable source of human adult mesenchymal progenitors when adipose tissue is used as a cell source

The Dichotomous Role of Inflammation in the CNS: A Mitochondrial Point of View

Innate immune response is one of our primary defenses against pathogens infection, although, if dysregulated, it represents the leading cause of chronic tissue inflammation. This dualism is even more present in the central nervous system, where neuroinflammation is both important for the activation of reparatory mechanisms and, at the same time, leads to the release of detrimental factors that induce neurons loss. Key players in modulating the neuroinflammatory response are mitochondria. Indeed, they are responsible for a variety of cell mechanisms that control tissue homeostasis, such as autophagy, apoptosis, energy production, and also inflammation. Accordingly, it is widely recognized that mitochondria exert a pivotal role in the development of neurodegenerative diseases, such as multiple sclerosis, Parkinson’s and Alzheimer’s diseases, as well as in acute brain damage, such in ischemic stroke and epileptic seizures. In this review, we will describe the role of mitochondria molecular signaling in regulating neuroinflammation in central nervous system (CNS) diseases, by focusing on pattern recognition receptors (PRRs) signaling, reactive oxygen species (ROS) production, and mitophagy, giving a hint on the possible therapeutic approaches targeting mitochondrial pathways involved in inflammation

Tissue-Specific Cultured Human Pericytes: Perivascular Cells from Smooth Muscle Tissue Have Restricted Mesodermal Differentiation Ability

Microvascular pericytes (PCs) are considered the adult counterpart of the embryonic mesoangioblasts, which represent a multipotent cell population that resides in the dorsal aorta of the developing embryo. Although PCs have been isolated from several adult organs and tissues, it is still controversial whether PCs from different tissues exhibit distinct differentiation potentials. To address this point, we investigated the differentiation potentials of isogenic human cultured PCs isolated from skeletal (sk-hPCs) and smooth muscle tissues (sm-hPCs). We found that both sk-hPCs and sm-hPCs expressed known pericytic markers and did not express endothelial, hematopoietic, and myogenic markers. Both sk-hPCs and sm-hPCs were able to differentiate into smooth muscle cells. In contrast, sk-hPCs, but not sm-hPCs, differentiated in skeletal muscle cells and osteocytes. Given the reported ability of the Notch pathway to regulate skeletal muscle and osteogenic differentiation, sk-hPCs and sm-hPCs were treated with N-[N-(3,5- difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a known inhibitor of Notch signaling. DAPT treatment, as assessed by histological and molecular analysis, enhanced myogenic differentiation and abolished osteogenic potential of sk-hPCs. In contrast, DAPT treatment did not affect either myogenic or osteogenic differentiation of sm-hPCs. In summary, these results indicate that, despite being isolated from the same anatomical niche, cultured PCs from skeletal muscle and smooth muscle tissues display distinct differentiation abilities