Insights into the Cellular and Molecular Mechanisms That Govern the Fracture-Healing Process: A Narrative Review

Fracture-healing is a complex multi-stage process that usually progresses flawlessly, resulting in restoration of bone architecture and function. Regrettably, however, a considerable number of fractures fail to heal, resulting in delayed unions or non-unions. This may significantly impact several aspects of a patient’s life. Not surprisingly, in the past few years, a substantial amount of research and number of clinical studies have been designed, aiming at shedding light into the cellular and molecular mechanisms that regulate fracture-healing. Herein, we present the current knowledge on the pathobiology of the fracture-healing process. In addition, the role of skeletal cells and the impact of marrow adipose tissue on bone repair is discussed. Unveiling the pathogenetic mechanisms that govern the fracture-healing process may lead to the development of novel, smarter, and more effective therapeutic strategies for the treatment of fractures, especially of those with large bone defects.

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Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

International Journal of Molecular Sciences ◽

10.3390/ijms22083955 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3955

Author(s):

László Bálint ◽

Zoltán Jakus

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Cell Fate ◽

Molecular Mechanisms ◽

Critical Role ◽

Mechanical Forces ◽

Lymphatic Endothelial Cells ◽

Lymphatic Development ◽

And Function ◽

The Impact

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

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The Cross-Talk between Mesenchymal Stem Cells and Immune Cells in Tissue Repair and Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms22052472 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2472

Author(s):

Carl Randall Harrell ◽

Valentin Djonov ◽

Vladislav Volarevic

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Immune Cells ◽

Tissue Repair ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Multipotent Stem Cells ◽

Tissue Repair And Regeneration ◽

Almost All ◽

And Function

Mesenchymal stem cells (MSCs) are self-renewable, rapidly proliferating, multipotent stem cells which reside in almost all post-natal tissues. MSCs possess potent immunoregulatory properties and, in juxtacrine and paracrine manner, modulate phenotype and function of all immune cells that participate in tissue repair and regeneration. Additionally, MSCs produce various pro-angiogenic factors and promote neo-vascularization in healing tissues, contributing to their enhanced repair and regeneration. In this review article, we summarized current knowledge about molecular mechanisms that regulate the crosstalk between MSCs and immune cells in tissue repair and regeneration.

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Can Optimizing the Mechanical Environment Deliver a Clinically Significant Reduction in Fracture Healing Time?

Biomedicines ◽

10.3390/biomedicines9060691 ◽

2021 ◽

Vol 9 (6) ◽

pp. 691

Author(s):

Jan Barcik ◽

Devakara R. Epari

Keyword(s):

Fracture Healing ◽

Bone Healing ◽

Mechanical Stimulation ◽

Callus Formation ◽

Weight Bearing ◽

Healing Process ◽

Healing Time ◽

Mechanical Environment ◽

Clinically Significant ◽

The Impact

The impact of the local mechanical environment in the fracture gap on the bone healing process has been extensively investigated. Whilst it is widely accepted that mechanical stimulation is integral to callus formation and secondary bone healing, treatment strategies that aim to harness that potential are rare. In fact, the current clinical practice with an initially partial or non-weight-bearing approach appears to contradict the findings from animal experiments that early mechanical stimulation is critical. Therefore, we posed the question as to whether optimizing the mechanical environment over the course of healing can deliver a clinically significant reduction in fracture healing time. In reviewing the evidence from pre-clinical studies that investigate the influence of mechanics on bone healing, we formulate a hypothesis for the stimulation protocol which has the potential to shorten healing time. The protocol involves confining stimulation predominantly to the proliferative phase of healing and including adequate rest periods between applications of stimulation.

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The Impact of Medium Chain and Polyunsaturated ω-3-Fatty Acids on Amyloid-β Deposition, Oxidative Stress and Metabolic Dysfunction Associated with Alzheimer´s Disease

Antioxidants ◽

10.3390/antiox10121991 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1991

Author(s):

Janine Mett

Keyword(s):

Oxidative Stress ◽

Fatty Acids ◽

Energy Metabolism ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Membrane Integrity ◽

Amyloid Β ◽

The Elderly ◽

Medium Chain ◽

The Impact

Alzheimer’s disease (AD), the most common cause of dementia in the elderly population, is closely linked to a dysregulated cerebral lipid homeostasis and particular changes in brain fatty acid (FA) composition. The abnormal extracellular accumulation and deposition of the peptide amyloid-β (Aβ) is considered as an early toxic event in AD pathogenesis, which initiates a series of events leading to neuronal dysfunction and death. These include the induction of neuroinflammation and oxidative stress, the disruption of calcium homeostasis and membrane integrity, an impairment of cerebral energy metabolism, as well as synaptic and mitochondrial dysfunction. Dietary medium chain fatty acids (MCFAs) and polyunsaturated ω-3-fatty acids (ω-3-PUFAs) seem to be valuable for disease modification. Both classes of FAs have neuronal health-promoting and cognition-enhancing properties and might be of benefit for patients suffering from mild cognitive impairment (MCI) and AD. This review summarizes the current knowledge about the molecular mechanisms by which MCFAs and ω-3-PUFAs reduce the cerebral Aβ deposition, improve brain energy metabolism, and lessen oxidative stress levels.

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New Insights on the Effects of Dietary Omega-3 Fatty Acids on Impaired Skin Healing in Diabetes and Chronic Venous Leg Ulcers

Foods ◽

10.3390/foods10102306 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2306

Author(s):

Simona Serini ◽

Gabriella Calviello

Keyword(s):

Fatty Acids ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Healing Process ◽

Vascular Diseases ◽

Lower Limbs ◽

Bioactive Metabolites ◽

Omega 3 ◽

Patients With Diabetes ◽

Skin Healing

Long-chain Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs) are widely recognized as powerful negative regulators of acute inflammation. However, the precise role exerted by these dietary compounds during the healing process is still largely unknown, and there is increasing interest in understanding their specific effects on the implicated cells/molecular factors. Particular attention is being focused also on their potential clinical application in chronic pathologies characterized by delayed and impaired healing, such as diabetes and vascular diseases in lower limbs. On these bases, we firstly summarized the current knowledge on wound healing (WH) in skin, both in normal conditions and in the setting of these two pathologies, with particular attention to the cellular and molecular mechanisms involved. Then, we critically reviewed the outcomes of recent research papers investigating the activity exerted by Omega-3 PUFAs and their bioactive metabolites in the regulation of WH in patients with diabetes or venous insufficiency and showing chronic recalcitrant ulcers. We especially focused on recent studies investigating the mechanisms through which these compounds may act. Considerations on the optimal dietary doses are also reported, and, finally, possible future perspectives in this area are suggested.

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Collaborative Technologies and Innovation in SMEs

Interdisciplinary Perspectives on E-Collaboration ◽

10.4018/978-1-61520-676-6.ch012 ◽

2010 ◽

pp. 204-217

Author(s):

Angel L. Meroño-Cerdan ◽

Pedro Soto-Acosta ◽

Carolina Lopez-Nicolas

Keyword(s):

The Other ◽

Research Model ◽

Firm Level ◽

Collaborative Technologies ◽

Other Hand ◽

Multi Stage ◽

Stage Process ◽

The One ◽

The Impact ◽

The Relationship

This study seeks to assess the impact of collaborative technologies on innovation at the firm level. Collaborative technologies’ influence on innovation is considered here as a multi-stage process that starts at adoption and extends to use. Thus, the effect of collaborative technologies on innovation is examined not only directly, the simple presence of collaborative technologies, but also based on actual collaborative technologies’ use. Given the fact that firms can use this technology for different purposes, collaborative technologies’ use is measured according to three orientations: e-information, e-communication and e-workflow. To achieve these objectives, a research model is developed for assessing, on the one hand, the impact of the adoption and use of collaborative technologies on innovation and, on the other hand, the relationship between adoption and use of collaborative technologies. The research model is tested using a dataset of 310 Spanish SMEs. The results showed that collaborative technologies’ adoption is positively related to innovation. Also, as hypothesized, distinct collaborative technologies were found to be associated to different uses. In addition, the study found that while e-information had a positive and significant impact on innovation, e-communication and e-workflow did not.

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Interferon β-Mediated Protective Functions of Microglia in Central Nervous System Autoimmunity

International Journal of Molecular Sciences ◽

10.3390/ijms20010190 ◽

2019 ◽

Vol 20 (1) ◽

pp. 190 ◽

Cited By ~ 7

Author(s):

Stefanie Scheu ◽

Shafaqat Ali ◽

Ritu Mann-Nüttel ◽

Lisa Richter ◽

Volker Arolt ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Molecular Mechanisms ◽

Chronic Inflammatory Disease ◽

Clinical Severity ◽

Interferon Β ◽

Treatment Regimens ◽

Cns Autoimmunity ◽

And Function ◽

The Impact

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and axonal damage. It often affects young adults and can lead to neurological disability. Interferon β (IFNβ) preparations represent widely used treatment regimens for patients with relapsing-remitting MS (RRMS) with therapeutic efficacy in reducing disease progression and frequency of acute exacerbations. In mice, IFNβ therapy has been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS while genetic deletion of IFNβ or its receptor augments clinical severity of disease. However, the complex mechanism of action of IFNβ in CNS autoimmunity has not been fully elucidated. Here, we review our current understanding of the origin, phenotype, and function of microglia and CNS immigrating macrophages in the pathogenesis of MS and EAE. In addition, we highlight the emerging roles of microglia as IFNβ-producing cells and vice versa the impact of IFNβ on microglia in CNS autoimmunity. We finally discuss recent progress in unraveling the underlying molecular mechanisms of IFNβ-mediated effects in EAE.

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Much More Than a Scaffold: Cytoskeletal Proteins in Neurological Disorders

Cells ◽

10.3390/cells9020358 ◽

2020 ◽

Vol 9 (2) ◽

pp. 358 ◽

Cited By ~ 9

Author(s):

Diana C. Muñoz-Lasso ◽

Carlos Romá-Mateo ◽

Federico V. Pallardó ◽

Pilar Gonzalez-Cabo

Keyword(s):

Neurological Disorders ◽

Actin Filaments ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Neurological Diseases ◽

Three Dimensional ◽

Cytoskeletal Proteins ◽

Dimensional Lattice ◽

New Treatments ◽

And Function

Recent observations related to the structure of the cytoskeleton in neurons and novel cytoskeletal abnormalities involved in the pathophysiology of some neurological diseases are changing our view on the function of the cytoskeletal proteins in the nervous system. These efforts allow a better understanding of the molecular mechanisms underlying neurological diseases and allow us to see beyond our current knowledge for the development of new treatments. The neuronal cytoskeleton can be described as an organelle formed by the three-dimensional lattice of the three main families of filaments: actin filaments, microtubules, and neurofilaments. This organelle organizes well-defined structures within neurons (cell bodies and axons), which allow their proper development and function through life. Here, we will provide an overview of both the basic and novel concepts related to those cytoskeletal proteins, which are emerging as potential targets in the study of the pathophysiological mechanisms underlying neurological disorders.

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Stromal vascular fraction promotes migration of fibroblasts and angiogenesis through regulation of extracellular matrix in the skin wound healing process

Stem Cell Research & Therapy ◽

10.1186/s13287-019-1415-6 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 8

Author(s):

Hongsen Bi ◽

Hui Li ◽

Chen Zhang ◽

Yiqing Mao ◽

Fangfei Nie ◽

...

Keyword(s):

Wound Healing ◽

Endothelial Cells ◽

Molecular Mechanisms ◽

Umbilical Vein ◽

Healing Process ◽

Stromal Vascular Fraction ◽

Wound Healing Process ◽

Matrix Remodeling ◽

Skin Defect ◽

The Impact

Abstract Background A refractory wound is a typical complication of diabetes and is a common outcome after surgery. Current approaches have difficulty in improving wound healing. Recently, non-expanded stromal vascular fraction (SVF), which is derived from mature fat, has opened up new directions for the treatment of refractory wound healing. The aim of the current study is to systematically investigate the impact of SVF on wound healing, including the rate and characteristics of wound healing, ability of fibroblasts to migrate, and blood transport reconstruction, with a special emphasis on their precise molecular mechanisms. Methods SVF was isolated by digestion, followed by filtration and centrifugation, and then validated by immunocytochemistry, a MTS proliferation assay and multilineage potential analysis. A wound model was generated by creating 6-mm-diameter wounds, which include a full skin defect, on the backs of streptozocin-induced hyperglycemic mice. SVF or human adipose-derived stem cell (hADSC) suspensions were subcutaneously injected, and the wounds were characterized over a 9-day period by photography and measurements. A scratch test was used to determine whether changes in the migratory ability of fibroblasts occurred after co-culture with hADSCs. Angiogenesis was observed with human umbilical vein endothelial cells. mRNA from fibroblasts, endotheliocyte, and skin tissue were sequenced by high-throughput RNAseq, and differentially expressed genes, and pathways, potentially regulated by SVF or hADSCs were bioinformatically analyzed. Results Our data show that hADSCs have multiple characteristics of MSC. SVF and hADSCs significantly improved wound healing in hyperglycemic mice. hADSCs improve the migratory ability of fibroblasts and capillary structure formation in HUVECs. SVF promotes wound healing by focusing on angiogenesis and matrix remodeling. Conclusions Both SVF and hADSCs improve the function of fibroblast and endothelial cells, regulate gene expression, and promote skin healing. Various mechanisms likely are involved, including migration of fibroblasts, tubulogenesis of endothelial cells through regulation of cell adhesion, and cytokine pathways.

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Molecular Mechanisms of Topography Sensing by Osteoblasts: An Update

Applied Sciences ◽

10.3390/app11041791 ◽

2021 ◽

Vol 11 (4) ◽

pp. 1791

Author(s):

Pablo Rougerie ◽

Rafaela Silva dos Santos ◽

Marcos Farina ◽

Karine Anselme

Keyword(s):

Cell Biology ◽

Bone Repair ◽

Molecular Mechanisms ◽

Cell Types ◽

Flat Surfaces ◽

Total Potential ◽

Gene Expression Matrix ◽

Specialized Tissue ◽

The Impact

Bone is a specialized tissue formed by different cell types and a multiscale, complex mineralized matrix. The architecture and the surface chemistry of this microenvironment can be factors of considerable influence on cell biology, and can affect cell proliferation, commitment to differentiation, gene expression, matrix production and/or composition. It has been shown that osteoblasts encounter natural motifs in vivo, with various topographies (shapes, sizes, organization), and that cell cultures on flat surfaces do not reflect the total potential of the tissue. Therefore, studies investigating the role of topographies on cell behavior are important in order to better understand the interaction between cells and surfaces, to improve osseointegration processes in vivo between tissues and biomaterials, and to find a better topographic surface to enhance bone repair. In this review, we evaluate the main available data about surface topographies, techniques for topographies’ production, mechanical signal transduction from surfaces to cells and the impact of cell–surface interactions on osteoblasts or preosteoblasts’ behavior.

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