Mammals have limited regenerative capacity, whereas some vertebrates, like fish and salamanders, are able to regenerate their organs efficiently. The regeneration in these species depends on cell dedifferentiation followed by proliferation. We generate a mouse model that enables the inducible expression of the four Yamanaka factors (Oct-3/4, Sox2, Klf4, and c-Myc, or 4F) specifically in hepatocytes. Transient in vivo 4F expression induces partial reprogramming of adult hepatocytes to a progenitor state and concomitantly increases cell proliferation. This is indicated by reduced expression of differentiated hepatic-lineage markers, an increase in markers of proliferation and chromatin modifiers, global changes in DNA accessibility, and an acquisition of liver stem and progenitor cell markers. Functionally, short-term expression of 4F enhances liver regenerative capacity through topoisomerase2-mediated partial reprogramming. Our results reveal that liver-specific 4F expression in vivo induces cellular plasticity and counteracts liver failure, suggesting that partial reprogramming may represent an avenue for enhancing tissue regeneration.

The characterization process of a new porous Nurse’s A ceramic and the physico chemical nature of the remodeled interface between the implant and the surrounding bone were studied after in vivo implantation. Scaffolds were prepared by a solid-state reaction and implanted in New Zealand rabbits. Animals were sacrificed on days 15, 30, and 60. The porous biomaterial displayed biocompatible, bioresorbable, and osteoconductive capacity. The degradation processes of implants also encouraged osseous tissue ingrowths into the material’s pores, and drastically changed the macro- and microstructure of the implants. After 60 healing days, the resorption rates were 52.62% ± 1.12% for the ceramic and 47.38% ± 1.24% for the residual biomaterial. The elemental analysis showed a gradual diffusion of the Ca and Si ions from the materials into the newly forming bone during the biomaterial’s resorption process. The energy dispersive spectroscopy (EDS) analysis of the residual ceramic revealed some particle categories with different mean Ca/P ratios according to size, and indicated various resorption process stages. Since osteoconductive capacity was indicated for this material and bone ingrowth was possible, it could be applied to progressively substitute an implant.

A new type of bioceramic with osteogenic properties, suitable for hard tissue regeneration, was synthesised. The ceramic was designed and obtained in the Nurse’s A-phase-silicocarnotite subsystem. The selected composition was that corresponding to the eutectoid 28.39 wt % Nurse’s A-phase-71.61 wt % silicocarnotite invariant point. We report the effect of Nurse’s A-phase-silicocarnotite ceramic on the capacity of multipotent adult human mesenchymal stem cells (ahMSCs) cultured under experimental conditions, known to adhere, proliferate and differentiate into osteoblast lineage cells. The results at long-term culture (28 days) on the material confirmed that the undifferentiated ahMSCs cultured and in contact with the material surface adhered, spread, proliferated, and produced a mineralised extracellular matrix on the studied ceramic, and finally acquired an osteoblastic phenotype. These findings indicate that it underwent an osteoblast differentiation process. All these findings were more significant than when cells were grown on plastic, in the presence and absence of this osteogenic supplement, and were more evident when this supplement was present in the growth medium (GM). The ceramic evaluated herein was bioactive, cytocompatible and capable of promoting the proliferation and differentiation of undifferentiated ahMSCs into osteoblasts, which may be important for bone integration into the clinical setting.

Calcium phosphate materials are widely used as bone substitutes due to their bioactive and biodegradable properties. Also, the presence of silicon in their composition seems to improve the bioactivity of the implant and promote bone tissue repair. The aim of this study was to develop a novel ceramic scaffold by partial solid-state sintering method with a composition lying in the field of the Nurse’s A-phase–silicocarnotite, in the tricalcium phosphate–dicalcium silicate (TCP–C₂S) binary system. Also, we evaluated its osteogenic and osteoconductive properties after being implanted into tibia defects in New Zealand rabbits. X-ray, microcomputer tomography, and histomorphometry studies demonstrated that this porous ceramic is highly biocompatible and it has excellent osteointegration. The material was being progressively reabsorbed throughout the study and there was no unspecified local or systemic inflammatory response observed. These results suggest that ceramic imitates the physicochemical characteristics of bone substitutes used in bone reconstruction.

This work evaluates in vitro the influence of a new biocompatible porous Si-Ca-P monophasic (7CaO·P₂O₅·2SiO₂) ceramic on the cellular metabolic activity, morphology and osteogenic differentiation of adult human mesenchymal stem cells (ahMSCs) cultured in basal growth medium and under osteogenic inductive medium. Alamar Blue Assay and FESEM were carried out in order to monitor the cell proliferation and the shape of the cells growing on the Si-Ca-P monophasic ceramic during the study period. The osteogenic differentiation of ahMSCs was investigated by means of immunofluorescent staining (osteocalcin, osteopontin, heparan sulphate and collagen type I expression), quantitative reverse transcription polymerase chain reaction (qRT-PCR) (integrin-binding sialoprotein, osteocalcin, alkaline phosphatase, osteopontin, osteonectin, runt-related transcription factor 2 and collagen type I) and expression of surface markers (CD73, CD90 and CD105). We could check osteogenic differentiation in ahMSCs growing under the influence of Si-Ca-P monophasic ceramics itself, but especially when growth medium was replaced by osteogenic medium in the culture conditions. These results allowed us to conclude that the new Si-Ca-P monophasic scaffold greatly enhanced ahMSCs proliferation and osteogenic differentiation; therefore, it may be considered to be employed as a new bone graft substitute or scaffold for bone tissue engineering.

Cardiorenal diseases represent a complex interplay between heart failure and renal dysfunction, being clinically classified as cardiorenal syndromes (CRS). Recently, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism, through deficient NAD+ synthesis and/or elevated consumption, have proved to be decisive in the onset and progress of cardiorenal disease. NAD+ is a pivotal coenzyme in cellular metabolism, being significant in various signaling pathways, such as energy metabolism, DNA damage repair, gene expression, and stress response. Convincing evidence suggests that strategies designed to boost cellular NAD+ levels are a promising therapeutic option to address cardiovascular and renal disorders. Here, we review and discuss the implications of NAD+ metabolism in cardiorenal diseases, focusing on the propitious NAD+ boosting therapeutic strategies, based on the use of NAD+ precursors, poly(ADP-ribose) polymerase inhibitors, sirtuin activators, and other alternative approaches, such as CD38 blockade, nicotinamide phosphoribosyltransferase activation and combined interventions.