Multiple myeloma (MM) is a malignancy of terminally-differentiated plasma cells that develops mainly inside the bone marrow (BM) microenvironment. It is well known that autocrine and paracrine signals are responsible for the progression of this disease but the precise mechanism and contributions from single cell remain largely unknown. Mesenchymal stem cells (MSC) are an important cellular component of the BM: they support MM growth by increasing its survival and chemo-resistance, but little is known about the paracrine signaling pathways. Three-dimensional (3D) models of MM-MSC paracrine interactions are much more biologically-relevant than simple 2D models and are considered essential for detailed studies of MM pathogenesis. Herein we present a novel 3D co-culture model designed to mimic the paracrine interaction between MSC and MM cells. MSC were embedded within a previously characterized thermoresponsive block copolymer worm gel that can induce stasis in human pluripotent stem cells (hPSC) and then co-cultured with MM cells. Transcriptional phenotyping of co-cultured cells indicated the dysregulation of genes that code for known disease-relevant factors, and also revealed IL-6 and IL-10 as upstream regulators. Importantly, we have identified a synergistic paracrine signaling pathway between IL-6 and IL-10 that plays a critical role in sustaining MM cell proliferation. Our findings indicate that this 3D co-culture system is a useful model to investigate the paracrine interaction between MM cells and the BM microenvironment in vitro. This approach has revealed a new mechanism that promotes the proliferation of MM cells and suggested a new therapeutic target.

The rising incidence of non-ST-segment elevation myocardial infarction (NSTEMI) and associated long-term high mortality constitutes an urgent clinical issue. Unfortunately, the study of possible interventions to treat this pathology lacks a reproducible pre-clinical model. Indeed, currently adopted small and large animal models of MI mimic only full-thickness, ST-segment-elevation (STEMI) infarcts, and hence cater only for an investigation into therapeutics and interventions directed at this subset of MI. Thus, we develop an ovine model of NSTEMI by ligating the myocardial muscle at precise intervals parallel to the left anterior descending coronary artery. Upon histological and functional investigation to validate the proposed model and comparison with STEMI full ligation model, RNA-seq and proteomics show the distinctive features of post-NSTEMI tissue remodelling. Transcriptome and proteome-derived pathway analyses at acute (7 days) and late (28 days) post-NSTEMI pinpoint specific alterations in cardiac post-ischaemic extracellular matrix. Together with the rise of well-known markers of inflammation and fibrosis, NSTEMI ischaemic regions show distinctive patterns of complex galactosylated and sialylated N-glycans in cellular membranes and extracellular matrix. Identifying such changes in molecular moieties accessible to infusible and intra-myocardial injectable drugs sheds light on developing targeted pharmacological solutions to contrast adverse fibrotic remodelling.

Heart failure (HF) is a clinical condition defined by structural and functional abnormalities in the heart that gradually result in reduced cardiac output (HFrEF) and/or increased cardiac pressures at rest and under stress (HFpEF). The presence of asymptomatic individuals hampers HF identification, resulting in delays in recognizing patients until heart dysfunction is manifested, thus increasing the chance of poor prognosis. Given the recent advances in metabolomics, in this review we dissect the main alterations occurring in the metabolic pathways behind the decrease in cardiac function caused by HF. Indeed, relevant preclinical and clinical research has been conducted on the metabolite connections and differences between HFpEF and HFrEF. Despite these promising results, it is crucial to note that, in addition to identifying single markers and reliable threshold levels within the healthy population, the introduction of composite panels would strongly help in the identification of those individuals with an increased HF risk. That said, additional research in the field is required to overcome the current drawbacks and shed light on the pathophysiological changes that lead to HF. Finally, greater collaborative data sharing, as well as standardization of procedures and approaches, would enhance this research field to fulfil its potential.

The ability of the zebrafish heart to regenerate following injury makes it a valuable model to deduce why this capability in mammals is limited to early neonatal stages. Although metabolic reprogramming and glycosylation remodeling have emerged as key aspects in many biological processes, how they may trigger a cardiac regenerative response in zebrafish is still a crucial question. Here, by using an up-to-date panel of transcriptomic, proteomic and glycomic approaches, we identify a metabolic switch from mitochondrial oxidative phosphorylation to glycolysis associated with membrane glycosylation remodeling during heart regeneration. Importantly, we establish the N- and O-linked glycan structural repertoire of the regenerating zebrafish heart, and link alterations in both sialylation and high mannose structures across the phases of regeneration. Our results show that metabolic reprogramming and glycan structural remodeling are potential drivers of tissue regeneration after cardiac injury, providing the biological rationale to develop novel therapeutics to elicit heart regeneration in mammals.

Background: Mesenchymal stem/stromal cells (MSC) have been employed successfully in immunotherapy and regenerative medicine, but their therapeutic potential is reduced considerably by the ischemic environment that exists after transplantation. The assumption that preconditioning MSC to promote quiescence may result in increased survival and regenerative potential upon transplantation is gaining popularity. Methods: The purpose of this work was to evaluate the anti-inflammatory and regenerative effects of human bone marrow MSC (hBM-MSC) and their extracellular vesicles (EVs) grown and isolated in a serum-free medium, as compared to starved hBM-MSC (preconditioned) in streptozotocin-induced diabetic fractured male C57BL/6J mice. Results: Blood samples taken four hours and five days after injection revealed that cells, whether starved or not, generated similar plasma levels of inflammatory-related cytokines but lower levels than animals treated with EVs. Nonetheless, starved cells prompted the highest production of IL-17, IL-6, IL-13, eotaxin and keratinocyte-derived chemokines and induced an earlier soft callus formation and mineralization of the fracture site compared to EVs and regularly fed cells five days after administration. Conclusions: Preconditioning may be crucial for refining and defining new criteria for future MSC therapies. Additionally, the elucidation of mechanisms underpinning an MSC’s survival/adaptive processes may result in increased cell survival and enhanced therapeutic efficacy following transplantation.

Background: Although the influence of titanium implants’ micro-surface properties on titanium discs has been extensively investigated, the research has not taken into consideration their whole-body effect, which may be considered possible using a combinatorial approach. Methods: Five titanium dental implants with a similar moderate roughness and different surface textures were thoroughly characterized. The cell adhesion and proliferation were assessed after adipose-tissue-derived stem cells (ADSCs) were seeded on whole-body implants. The implants’ inductive properties were assessed by evaluating the osteoblastic gene expression. Results: The surface micro-topography was analyzed, showing that hydroxyapatite (HA)-blasted and bland acid etching implants had the highest roughness and a lower number of surface particles. Cell adhesion was observed after 24 h on all the implants, with the highest score registered for the HA-blasted and bland acid etching implants. Cell proliferation was observed only on the laser-treated and double-acid-etched surfaces. The ADSCs expressed collagen type I, osteonectin, and alkaline phosphatase on all the implant surfaces, with high levels on the HA-treated surfaces, which also triggered osteocalcin expression on day seven. Conclusions: The findings of this study show that the morphology and treatment of whole titanium dental implants, primarily HA-treated and bland acid etching implants, impact the adherence and activity of ADSCs in osteogenic differentiation in the absence of specific osteo-inductive signals.