A comprehensive molecular profiling approach reveals metabolic alterations that steer bone tissue regeneration.

Bone regeneration after fracture is a complex process with high and dynamic energy demands. The impact of metabolism on bone healing progression and outcome, however, is so far understudied. Our comprehensive molecular profiling reveals that central metabolic pathways, such as glycolysis and the citric acid cycle, are differentially activated between rats with successful or compromised bone regeneration (young versus aged female Sprague-Dawley rats) early in the inflammatory phase of bone healing.

High glucose impairs osteogenic differentiation of embryonic stem cells via early diversion of beta-catenin from Forkhead box O to T cell factor interaction.

Background: Diabetes, which is characterized by an increase in blood glucose concentration, is accompanied by low bone turnover, increased fracture risk, and the formation of embryonic skeletal malformations. Yet, there are few studies elucidating the underlying alterations in signaling pathways leading to these osteogenic defects. We hypothesized here that bone formation deficiencies in a high glucose environment result from altered activity of beta-catenin (CTNNB1), a key contributor to osteogenic differentiation, dysregulation of which has also been implicated in the development of diabetes.

Alginate Hydrogels for Bone Regeneration: The Immune Competence of the Animal Model Matters.

Biomaterials with tunable biophysical properties hold great potential for tissue engineering. The adaptive immune system plays an important role in bone regeneration. Our goal is to investigate the regeneration potential of cell-laden alginate hydrogels depending on the immune status of the animal model.

Bioactive coating of zirconia toughened alumina ceramic implants improves cancellous osseointegration.

Bioactive coatings have the potential to improve the bony integration of mechanically loaded orthopedic ceramic implants. Using the concept of mimicking the natural bone surface, four different coatings of varying thickness on a zirconia toughened alumina (ZTA) ceramic implant were investigated regarding their osseointegration in a drill-hole model in sheep. The hypothesis that a bioactive coating of ZTA ceramics would facilitate cancellous bone integration was investigated.

Compromised Bone Healing in Aged Rats Is Associated With Impaired M2 Macrophage Function.

Fracture repair is initiated by a multitude of immune cells and induction of an inflammatory cascade. Alterations in the early healing response due to an aged adaptive immune system leads to impaired bone repair, delayed healing or even formation of non-union. However, immuno-senescence is not limited to the adaptive immunity, but is also described for macrophages, main effector cells from the innate immune system.

Circulating dipeptidyl peptidase 3 is a myocardial depressant factor: dipeptidyl peptidase 3 inhibition rapidly and sustainably improves haemodynamics.

Aims: Acute heart failure is a high mortality disease and its pathophysiology is not completely understood. Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in angiotensin II and enkephalins cleavage. The aim of this study was to investigate the association of circulating DPP3 (cDPP3) levels and mortality in cardiogenic shock patients and to determine the effects of high cDPP3 on organ function in a heart failure (HF) model in mice.

A novel and highly efficient purification procedure for native human dipeptidyl peptidase 3 from human blood cell lysate.

Dipeptidyl amino-peptidase 3 (DPP3) is an aminopeptidase involved in peptide degradation, including hormone peptides as angiotensin II and enkephalins. DPP3 plasma activity increases in septic patients and correlates with mortality risk. However, the exact physiological role of DPP3 remains unclear and animal studies are necessary to reveal the function of DPP3 in vivo.

The Metabolic Microenvironment Steers Bone Tissue Regeneration.

Over the past years, basic findings in cancer research have revealed metabolic symbiosis between different cell types to cope with high energy demands under limited nutrient availability. Although this also applies to regenerating tissues with disrupted physiological nutrient and oxygen supply, the impact of this metabolic cooperation and metabolic reprogramming on cellular development, fate, and function during tissue regeneration has widely been neglected so far. With this review, we aim to provide a schematic overview on metabolic links that have a high potential to drive tissue regeneration.

In-situ tissue regeneration through SDF-1α driven cell recruitment and stiffness-mediated bone regeneration in a critical-sized segmental femoral defect.

Unlabelled: In-situ tissue regeneration aims to utilize the body's endogenous healing capacity through the recruitment of host stem or progenitor cells to an injury site. Stromal cell-derived factor-1α (SDF-1α) is widely discussed as a potent chemoattractant. Here we use a cell-free biomaterial-based approach to (i) deliver SDF-1α for the recruitment of endogenous bone marrow-derived stromal cells (BMSC) into a critical-sized segmental femoral defect in rats and to (ii) induce hydrogel stiffness-mediated osteogenic differentiation in-vivo.

Biophysical induction of cell release for minimally manipulative cell enrichment strategies.

The use of autologous cells harvested and subsequently transplanted in an intraoperative environment constitutes a new approach to promote regeneration. Usually cells are isolated by selection methods such as fluorescence- or magnetic- activated cell sorting with residual binding of the antibodies or beads. Thus, cell-based therapies would benefit from the development of new devices for cell isolation that minimally manipulate the target cell population.

CD31+ Cells From Peripheral Blood Facilitate Bone Regeneration in Biologically Impaired Conditions Through Combined Effects on Immunomodulation and Angiogenesis.

Controlled revascularization and inflammation are key elements regulating endogenous regeneration after (bone) tissue trauma. Peripheral blood-derived cell subsets, such as regulatory T-helper cells and circulating (endothelial) progenitor cells, respectively, can support endogenous tissue healing, whereas effector T cells that are associated with an aged immune system can hinder bone regeneration. CD31 is expressed by diverse leukocytes and is well recognized as a marker of circulating endothelial (precursor) cells; however, CD31 is absent from the surface of differentiated effector T cells.

Influence of particulate and dissociated metal-on-metal hip endoprosthesis wear on mesenchymal stromal cells in vivo and in vitro.

In hip arthroplasty the implants' articulating surfaces can be made of a cobalt-chromium-molybdenum (CoCrMo) alloy. The use of these metal-on-metal (MoM) pairings can lead to the release of wear products such as metallic particles and dissociated metal species, raising concerns regarding their safety amongst orthopedic surgeons and the public. MoM-wear particles are reported to be heterogeneous in their physicochemical properties, are capable of inducing adverse effects on a cellular level and are thought to be involved in relevant clinical problems like aseptic osteolysis.

Macrophages in bone fracture healing: Their essential role in endochondral ossification.

In fracture healing, skeletal and immune system are closely interacting through common cell precursors and molecular mediators. It is thought that the initial inflammatory reaction, which involves migration of macrophages into the fracture area, has a major impact on the long term outcome of bone repair. Interestingly, macrophages reside during all stages of fracture healing.

Regulatory T cell-mediated anti-inflammatory effects promote successful tissue repair in both indirect and direct manners.

Regulatory T cells (Tregs) offer new immunotherapeutic options to control undesired immune reactions, such as those in transplant rejection and autoimmunity. In addition, tissue repair and regeneration depend on a multitude of tightly regulated immune and non-immune cells and signaling molecules. There is mounting evidence that adequate innate responses, and even more importantly balanced adaptive immune responses, are key players in the tissue repair and regeneration processes, even in absence of any immune-related disease or infection.

Accumulation of amino-polyvinyl alcohol-coated superparamagnetic iron oxide nanoparticles in bone marrow: implications for local stromal cells.

Aims: First, it will be investigated if amino-polyvinyl alcohol-coated superparamagnetic iron oxide nanoparticles (A-PVA-SPIONs) are suitable for MRI contrast enhancement in bone marrow. Second, the impact of A-PVA-SPION exposure in vivo on the viability and key functions of local bone marrow stromal cells (BMSCs) will be investigated.

Material & Methods: Animals were systemically injected with A-PVA-SPIONs, followed by a 7-day survival time.

High-dose recombinant human bone morphogenetic protein-2 impacts histological and biomechanical properties of a cervical spine fusion segment: results from a sheep model.

The 'off-label' use of high-dose recombinant human bone morphogenetic protein-2 (rhBMP-2) in lumbar and cervical fusion leads to heterotopic bone formation and vertebral osteolysis. These radiographically assessed side-effects in patients were frequently associated with an over-dosage of BMP-2. However, little is so far known about the histological, functional or biomechanical tissue consequences of over-dosage of rhBMP-2 in these specific clinical situations.

Amino-polyvinyl alcohol coated superparamagnetic iron oxide nanoparticles are suitable for monitoring of human mesenchymal stromal cells in vivo.

Mesenchymal stromal cells (MSCs) are promising candidates in regenerative cell-therapies. However, optimizing their number and route of delivery remains a critical issue, which can be addressed by monitoring the MSCs' bio-distribution in vivo using super-paramagnetic iron-oxide nanoparticles (SPIONs). In this study, amino-polyvinyl alcohol coated (A-PVA) SPIONs are introduced for cell-labeling and visualization by magnetic resonance imaging (MRI) of human MSCs.

Qualifying stem cell sources: how to overcome potential pitfalls in regenerative medicine?

Regenerative medicine aims to replace lost cells and to restore damaged tissues and organs by either tissue-engineering approaches or stimulation of endogenous processes. Due to their biological properties, stem cells promise to be an effective source for such strategies. Especially adult multipotent stem cells (ASCs) are believed to be applicable in a broad range of therapies for the treatment of multifactorial diseases or age-related degeneration, although the molecular and cellular mechanisms underlying their regenerative function are often hardly described.

Initiation and early control of tissue regeneration - bone healing as a model system for tissue regeneration.

Introduction: Tissue regeneration in itself is a fascinating process that promises repeated renewal of tissue and organs.

Areas Covered: This article aims to illustrate the different strategies available to control tissue regeneration at a very early stage, using bone as an exemplary tissue. The aspects of a controlled inflammatory cascade to achieve a balanced immune response, cell therapeutic approaches for improved tissue formation and angiogenesis, guiding the organization of newly formed extracellular matrix by biomaterials, the relevance of mechanical signals for tissue regeneration processes, and the chances and limitations of growth factor treatments are discussed.

In serum veritas-in serum sanitas? Cell non-autonomous aging compromises differentiation and survival of mesenchymal stromal cells via the oxidative stress pathway.

Even tissues capable of complete regeneration, such as bone, show an age-related reduction in their healing capacity. Here, we hypothesized that this decline is primarily due to cell non-autonomous (extrinsic) aging mediated by the systemic environment. We demonstrate that culture of mesenchymal stromal cells (MSCs) in serum from aged Sprague-Dawley rats negatively affects their survival and differentiation ability.

CD133: enhancement of bone healing by local transplantation of peripheral blood cells in a biologically delayed rat osteotomy model.

Sufficient angiogenesis is crucial during tissue regeneration and therefore also pivotal in bone defect healing. Recently, peripheral blood derived progenitor cells have been identified to have in addition to their angiogenic potential also osteogenic characteristics, leading to the hypothesis that bone regeneration could be stimulated by local administration of these cells. The aim of this study was to evaluate the angiogenic potential of locally administered progenitor cells to improve bone defect healing.

Absorption-based assays for the analysis of osteogenic and chondrogenic yield.

The typical characteristics of cartilage and bone tissue are their unique extracellular matrices on which our body relies for structural support. In the respective tissue, the cells that create these matrices are the chondrocyte and the osteoblast. During in vitro differentiation from an embryonic or any other stem cell, specific cell types must be unequivocally identifiable to be able to draw the conclusion that a specific cell type has indeed been generated.

Hyperglycemia impairs skeletogenesis from embryonic stem cells by affecting osteoblast and osteoclast differentiation.

High maternal blood glucose levels caused by diabetes mellitus can irreversibly lead to maldevelopment of the growing fetus with specific effects on the skeleton. To date, it remains controversial at which stage embryonic development is affected. Specifically during embryonic bone development, it is unclear whether diminished bone mineral density is caused by reduced osteoblast or rather enhanced osteoclast function.