The bone marrow (BM) niche is the spatial structure within the intra-trabecular spaces of spongious bones and of the cavity of long bones where adult haematopoietic stem cells (HSCs) maintain their ...undifferentiated and cellular self-renewal state through the intervention of vascular and nervous networks, metabolic pathways, transcriptional and epigenetic regulators, and humoral signals. Within the niche, HSCs interact with various cell types such as osteoblasts, endothelial cells, macrophages, and mesenchymal stromal cells (MSCs), which maintain HSCs in a quiescent state or sustain their proliferation, differentiation, and trafficking, depending on body needs. In physiological conditions, the BM niche permits the daily production of all the blood and immune cells and their admittance/ingress/progression into the bloodstream. However, disruption of this delicate microenvironment promotes the initiation and progression of malignancies such as those included in the spectrum of myeloid neoplasms, also favouring resistance to pharmacological therapies. Alterations in the MSC population and in the crosstalk with HSCs owing to tumour-derived factors contribute to the formation of a malignant niche. On the other hand, cells of the BM microenvironment cooperate in creating a unique milieu favouring metastasization of distant tumours into the bone. In this framework, the pro-tumorigenic role of MSCs is well-documented, and few evidence suggest also an anti-tumorigenic effect. Here we will review recent advances regarding the BM niche composition and functionality in normal and in malignant conditions, as well as the therapeutic implications of the interplay between its diverse cellular components and malignant cells.
The long pentraxin 3 (PTX3) is a soluble glycoprotein made by immune and nonimmune cells endowed with pleiotropic functions in innate immunity, inflammation, and tissue remodeling. PTX3 has recently ...emerged as a mediator of bone turnover in both physiological and pathological conditions, with direct and indirect effects on osteoblasts and osteoclasts. This notwithstanding, its role in bone biology, with major regard to the osteogenic potential of osteoblasts and their interplay with osteoclasts, is at present unclear. Here, we investigated the contribution of this pentraxin to bone deposition in the osteogenic lineage by assessing collagen production, mineralization capacity, osteoblast maturation, extracellular matrix gene expression, and inflammatory mediators' production in primary osteoblasts from the calvaria of wild-type (WT) and
-deficient (
) mice. Also, we evaluated the effect of PTX3 on osteoclastogenesis in cocultures of primary osteoblasts and bone marrow-derived osteoclasts. Our investigations were carried out both in physiological and inflammatory conditions to recapitulate in vitro aspects of inflammatory diseases of the bone. We found that primary osteoblasts from WT animals constitutively expressed low levels of the protein in osteogenic noninflammatory conditions, and genetic ablation of PTX3 in these cells had no major impact on collagen and hydroxyapatite deposition. However,
osteoblasts had an increased RANKL/OPG ratio and CD44 expression, which resulted in in enhanced osteoclastogenesis when cocultured with bone marrow monocytes. Inflammation (modelled through administration of tumor necrosis factor-α, TNF-α) boosted the expression and accumulation of PTX3 and inflammatory mediators in WT osteoblasts. In these conditions,
genetic depletion was associated with reduced collagen deposition and immune modulators' production. Our study shed light on the role of PTX3 in osteoblast and osteoclast biology and identified a major effect of inflammation on the bone-related properties of this pentraxin, which might be relevant for therapeutic and/or diagnostic purposes in musculoskeletal pathology.
Upon infection, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is predicted to interact with diverse cellular functions, such as the nonsense-mediated decay (NMD) pathway, as suggested ...by the identification of the core NMD factor upframeshift-1 (UPF1) in the SARS-CoV-2 interactome, and the retrograde transport from the Golgi to the endoplasmic reticulum (ER) through the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), where coronavirus assembly occurs. Here, we investigated the expression and localization of the neuroblastoma-amplified sequence (NBAS) protein, a UPF1 partner for the NMD at the ER, participating also in retrograde transport, and of its functional partners, at early time points after SARS-CoV-2 infection of the human lung epithelial cell line Calu3. We found a significant decrease of DExH-Box Helicase 34 (
, suppressor with morphogenetic effect on genitalia 5 (
, and
expression at 6 h post-infection, followed by a significant increase of these genes and also
and
at 9 h post-infection. Conversely,
and other genes coding for NMD factors were not modulated. Known NMD substrates related to cell stress (Growth Arrest Specific 5,
transducin beta-like 2,
; and DNA damage-inducible transcript 3,
) were increased in infected cells, possibly as a result of alterations in the NMD pathway and of a direct effect of the infection. We also found that the expression of unconventional SNARE in the ER 1,
(p31) and Zeste White 10 homolog,
, partners of NBAS in the retrograde transport function, significantly increased over time in infected cells. Co-localization of NBAS and UPF1 proteins did not change within 24 h of infection nor did it differ in infected versus non-infected cells at 1 and 24 h after infection; similarly, the co-localization of NBAS and p31 proteins was not altered by infection in this short time frame. Finally, both NBAS and UPF1 were found to co-localize with SARS-CoV-2 S and N proteins. Overall, these data are preliminary evidence of an interaction between NBAS and NBAS-related functions and SARS-CoV-2 in infected cells, deserving further investigation.
Periprosthetic joint infections (PJIs) are serious complications of prosthetic surgery. The criteria for the diagnosis of PJI integrate clinical and laboratory findings in a complex and sometimes ...inconclusive workflow. Host immune factors hold potential as diagnostic biomarkers in bone and joint infections. We reported that the humoral pattern-recognition molecule long pentraxin 3 (PTX3) predicts PJI in total hip and knee arthroplasty (THA and TKA, respectively). If and how genetic variation in
and inflammatory genes that affect its expression (
,
,
, and
) contributes to the risk of PJI is unknown. We conducted a case-control study on a Caucasian historic cohort of THA and TKA patients who had prosthesis explant due to PJI (cases) or aseptic complications (controls). Saliva was collected from 93 subjects and used to extract DNA and genotype
,
,
,
, and
single-nucleotide polymorphisms (SNPs). Moreover, the concentration of IL-1β, IL-10, and IL-6 was measured in synovial fluid and plasma. No association was found between
polymorphisms and PJI; however, the AGG haplotype, encompassing rs2853550, rs1143634, and rs1143627 in
, was linked to the infection (
= 0.017). Also, synovial levels of all inflammatory markers were higher in cases than in controls, and a correlation emerged between synovial concentration of PTX3 and that of IL-1β in cases only (Spearman r = 0.67,
= 0.004). We identified a relationship between rs2853550 and the synovial concentration of IL-1β and PTX3. Our findings suggest that
SNPs could be used for the early identification of THA and TKA patients with a high risk of infection.
Different from inflammatory arthritis, where biologicals and targeted synthetic molecules have revolutionized the disease course, no drug has demonstrated a disease modifying activity in ...osteoarthritis, which remains one of the most common causes of disability and chronic pain worldwide. The pharmacological therapy of osteoarthritis is mainly directed towards symptom and pain relief, and joint replacement is still the only curative strategy. Elucidating the disease pathophysiology is essential to understand which mechanisms can be targeted by innovative therapies. It has extensively been demonstrated that aberrant WNT and IL-1 signaling pathways are responsible for cartilage degeneration, impaired chondrocyte metabolism and differentiation, increased extracellular matrix degradation, and altered subchondral bone homeostasis. Platelet-rich plasma is an autologous blood derivative containing a concentration of platelets that is much higher than the whole blood counterpart and has shown promising results in the treatment of early knee osteoarthritis. Among the proposed mechanisms, the modulation of WNT and IL-1 pathways is of paramount importance and is herein reviewed in light of the proposed regenerative approaches.
ABSTRACT
The Transiting Exoplanet Survey Satellite (TESS) is focusing on relatively bright stars and has found thousands of planet candidates. However, mainly because of the low spatial resolution of ...its cameras (≈ 21 arcsec/pixel), TESS is expected to detect several false positives (FPs); hence, vetting needs to be done. Here, we present a follow-up program of TESS candidates orbiting solar-analogue stars that are in the all-sky PLATO input catalogue. Using Gaia photometry and astrometry we built an absolute colour–magnitude diagram and isolated solar-analogue candidates’ hosts. We performed a probabilistic validation of each candidate using the vespa software and produced a prioritized list of objects that have the highest probability of being genuine transiting planets. Following this procedure, we eliminated the majority of FPs and statistically vetted 23 candidates. For this remaining set, we performed a stellar neighbourhood analysis using Gaia Early Data Release 3 and centroid motion tests, greatly enhancing the on-target probability of 12 of them. We then used publicly available high-resolution imaging data to confirm their transit source and found five new, fully validated planets. For the remaining candidates, we propose on–off photometry to further refine the list of genuine candidates and prepare for the subsequent radial velocity follow-up.
The improvement of hematopoietic stem and progenitor cell (HSPC) engraftment remains a high-priority goal when limited cell doses are available, such as in cord blood (CB) transplantation and HSC ...gene therapy. We observed that monocytes are highly effective at improving the engraftment of both CB-CD34
and lentivirus-transfected CD34
cells in a xenogeneic model of HSC transplantation. Moreover, monocytes, in particular the CD14
CD16
classical subset, in co-culture systems increase survival and stemness of CB-CD34
cells. Both soluble factors and direct-cell contact interactions, such as JAG/NOTCH and COX-2/PGE2 pathways, are critically involved in the HSC-monocyte crosstalk. Our results indicate that the infusion of monocytes improves engraftment when cell dose is a limiting factor.
ABSTRACT
The Transiting Exoplanet Survey Satellite (TESS) and the upcoming mission PLAnetary Transits and Oscillations of stars (PLATO) represent two space-based missions with complementary ...objectives in the field of exoplanet science. While TESS aims at detecting and characterizing exoplanets around bright and nearby stars on a relative short-period orbit, PLATO will discover a wide range of exoplanets including rocky planets within the habitable zones of their stars. We analyse mono-transit events in TESS data around stars that will or could be monitored by the PLATO mission, offering a unique opportunity to bridge the knowledge gap between the two missions and gain deeper insights into exoplanet demographics and system architectures. We found 48 TESS mono-transit events around stars contained in the all-sky PLATO Input Catalog; of these, at least four will be imaged on the first long-pointing PLATO field, LOPS2. We uniformly vetted this sample to rule out possible false positive detections thus removing 10 signals from the original sample. We developed an analytic method which allows us to estimate both the orbital period and inclination of a mono-transit planet candidate using only the shape of the transit. We derived the orbital period and inclination estimates for 30 TESS mono-transit planet candidates. Finally, we investigated whether these candidates are amenable targets for a CHaracterising ExOPlanets Satellite observing campaign.
Tendon injuries are severe burdens in clinics. The poor tendon healing is related to an ineffective response of resident cells and inadequate vascularization. Thanks to the high proliferation and ...multi-lineage differentiation capability, bone marrow-derived mesenchymal stem cells (BMSCs) are a promising cell source to support the tendon repair. To date, the association of various growth factors to induce the in vitro tenogenic differentiation of multipotent progenitor cells is poorly investigated. This study aimed to investigate the tenogenic differentiation of rabbit BMSCs by testing the combination of bone morphogenetic proteins (BMP-12 and 14) with transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF) both in 2D and 3D cultures within fibrin-based constructs. After 7 and 14 days, the tenogenic differentiation was assessed by analyzing cell metabolism and collagen content, the gene expression of tenogenic markers and the histological cell distribution and collagen deposition within 3D constructs.
Our results demonstrated that the association of BMP-14 with TGF-β3 and VEGF enhanced the BMSC tenogenic differentiation both in 2D and 3D cultures. This study supports the use of fibrin as hydrogel-based matrix to generate spheroids loaded with tenogenic differentiated BMSCs that could be used to treat tendon lesions in the future.
We report a detailed characterization of the Kepler-19 system. This star was previously known to host a transiting planet with a period of 9.29 days, a radius of 2.2 R⊕, and an upper limit on the ...mass of 20 M⊕. The presence of a second, non-transiting planet was inferred from the transit time variations (TTVs) of Kepler-19b over eight quarters of Kepler photometry, although neither the mass nor period could be determined. By combining new TTVs measurements from all the Kepler quarters and 91 high-precision radial velocities obtained with the HARPS-N spectrograph, using dynamical simulations we obtained a mass of 8.4 1.6 M⊕ for Kepler-19b. From the same data, assuming system coplanarity, we determined an orbital period of 28.7 days and a mass of 13.1 2.7 M⊕ for Kepler-19c and discovered a Neptune-like planet with a mass of 20.3 3.4 M⊕ on a 63-day orbit. By comparing dynamical simulations with non-interacting Keplerian orbits, we concluded that neglecting interactions between planets may lead to systematic errors that can hamper the precision in the orbital parameters when the data set spans several years. With a density of 4.32 0.87 g cm−3 (0.78 0.16 ⊕) Kepler-19b belongs to the group of planets with a rocky core and a significant fraction of volatiles, in opposition to low-density planets characterized only by transit time variations and an increasing number of rocky planets with Earth-like density. Kepler-19 joins the small number of systems that reconcile transit timing variation and radial velocity measurements.
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