Paul T Sharpe's research while affiliated with The Czech Academy of Sciences and other places
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Publications (386)
Dysfunction of primary cilia leads to genetic disorder, ciliopathies, which shows various malformations in many vital organs such as brain. Multiple tongue deformities including cleft, hamartoma and ankyloglossia are also seen in ciliopathies, which yield difficulties in fundamental functions such as mastication and vocalization. Here, we found the...
The interplay among different cells in a tissue is essential for maintaining homeostasis. Although, disease states have been traditionally attributed to individual cell types, increasing evidence and new therapeutic options have demonstrated the primary role of multicellular functions to understand health and disease, opening new avenues to underst...
The term apoptosis, as a way of programmed cell death, was coined a half century ago and since its discovery the process has been extensively investigated. The anatomy and physiology of the head are complex and thus apoptosis has mostly been followed in separate structures, tissues or cell types. This review aims to provide a comprehensive overview...
Management of the growing adult orthodontic patient population must contend with challenges particular to orthodontic treatment in adults. These include a limited rate of tooth movement, increased incidence of periodontal complications, higher risk of iatrogenic root resorption and pulp devitalisation, resorbed edentulous ridges, and lack of growth...
With the proven relationship between oral and general health and the growing aging population, it is pivotal to provide accessible therapeutic approaches to regenerate oral tissues and restore clinical function. However, despite sharing many core concepts with medicine, dentistry has fallen behind the progress in precision medicine and regenerative...
Telocytes (TCs) or interstitial cells are characterised in vivo by their long projections that contact other cell types. Although telocytes can be found in many different tissues including the heart ¹ , lung ² and intestine ³ , their tissue-specific roles are poorly understood. Here we identify a specific cell signalling role for telocytes in the p...
Oral and craniofacial tissues are uniquely adapted for continuous and intricate functioning, including breathing, feeding, and communication. To achieve these vital processes, this complex is supported by incredible tissue diversity, variously composed of epithelia, vessels, cartilage, bone, teeth, ligaments, and muscles, as well as mesenchymal, ad...
Objective:
Single-cell transcriptomics was used to determine the possible cell-type specificity of periodontitis susceptibility genes.
Background:
The last decade has witnessed remarkable advances in the field of human genomics. Despite many advances, the genetic factors associated with or contributing to the periodontitis pathogenesis have only...
Objectives
To evaluate hydrogel-based scaffolds embedded with parathyroid hormone (PTH)-loaded mesoporous bioactive glass (MBG) on the enhancement of bone tissue regeneration in vitro.
Materials and methods
MBG was produced via sol–gel technique followed by PTH solution imbibition. PTH-loaded MBG was blended into the hydrogels and submitted to a l...
The interplay among different cells in a tissue is essential for maintaining homeostasis. Although, disease states have been traditionally attributed to individual cell types, increasing evidence and new therapeutic options have demonstrated the primary role of multicellular functions to understand health and disease, opening new avenues to underst...
The teeth and their supporting tissues provide an easily accessible source of oral stem cells. These different stem cell populations have been extensively studied for their properties, such as high plasticity and clonogenicity, expressing stem cell markers and potency for multilineage differentiation in vitro. Such cells with stem cell properties h...
Objectives:
The ciliopathies are a wide spectrum of human diseases, which are caused by perturbations in the function of primary cilia. Tooth enamel anomalies are often seen in ciliopathy patients; however, the role of primary cilia in enamel formation remains unclear.
Materials and methods:
We examined mice with epithelial conditional deletion...
Single-cell RNA-sequencing technologies have revolutionized the way that researchers can interrogate cellular relationships and the level of detail by which tissue architecture can be characterized. Multiple cell capturing methods have been developed that, when coupled to next-generation sequencing, can yield cell-to-cell specific information regar...
Periodontal disease is a significant burden for oral health, causing progressive and irreversible damage to the support structure of the tooth. This complex structure, the periodontium, is composed of interconnected soft and mineralised tissues, posing a challenge for regenerative approaches. Materials combining silicon and lithium are widely studi...
The periodontal ligament (PDL) is an essential tissue connecting teeth and bone. It is a complex tissue specifically designed to absorb the forces of mastication; analysis of its multiple cell populations is important to understand its function and the cell changes associated with periodontal disease. Cells in the periodontal ligament are not fully...
The vertebrate Dlx genes, generally organized as tail-to-tail bigene clusters, are expressed in the branchial arch epithelium and mesenchyme with nested proximodistal expression implicating a code that underlies the fates of jaws. Little is known of the regulatory architecture that is responsible for Dlx gene expression in developing arches. We hav...
Bidirectional transcription, leading to the expression of an antisense (AS) RNA partially complementary to the protein coding sense (S) RNA, is an emerging subject in mammals and has been associated with various processes such as RNA interference, imprinting and transcription inhibition. Homeobox genes do not escape this bidirectional transcription...
Teeth are complex structures where a soft dental pulp tissue is enriched with nerves, vasculature and connective tissue and encased by the cushioning effect of dentin and the protection of a hard enamel in the crown and cementum in the root. Injuries such as trauma or caries can jeopardise these layers of protection and result in pulp exposure, inf...
Small-molecule drugs targeting glycogen synthase kinase 3 (GSK3) as inhibitors of the protein kinase activity are able to stimulate reparative dentine formation. To develop this approach into a viable clinical treatment for exposed pulp lesions, we synthesized a novel, small-molecule noncompetitive adenosine triphosphate (ATP) drug that can be inco...
Engineering cytocompatible hydrogels with tunable physico-mechanical properties as a biomimetic three-dimensional extracellular matrix (ECM) is fundamental to guide cell response and target tissue regeneration or development of in vitro models. Gelatin represents an optimal choice given its ECM biomimetic properties; however, gelatin cross-linking...
Background
Telocytes (TCs) or interstitial cells are characterised in vivo by their long projections that contact other cell types. Although telocytes can be found in many different tissues in luding the heart ¹ , lung ² and intestine ³ , their tissue-specific roles are poorly understood. Here we identify a cell signalling role for telocytes in the...
Objectives:
Glass ionomer cements (GIC) can be used to protect dentine following caries removal. However, GIC have little biological activity on biological repair processes, which means that neo-dentine formation remains reliant on limited endogenous regenerative processes. Wnt/β-catenin signalling is known to play a central role in stimulating te...
Background
Mesenchymal stem cells (MSCs) are potential candidates for tissue engineering and regenerative medicine applications. Stromal tissues, from which MSCs are extracted, exist all over the body, suggesting that their precursors are locally available in multiple organs, providing a source of MSCs for homeostasis and repair of tissues. Teeth a...
Tissue engineering (TE) is a multidisciplinary research field aiming at the regeneration, restoration, or replacement of damaged tissues and organs. Classical TE approaches combine scaffolds, cells and soluble factors to fabricate constructs mimicking the native tissue to be regenerated. However, to date, limited success in clinical translations ha...
Bone tissue requires a range of complex mechanisms to allow the restoration of its structure and function. Bone healing is a signaling cascade process, involving cells secreting cytokines, growth factors, and pro-inflammatory factors in the defect site that will, subsequently, recruit surrounding stem cells to migrate, proliferate, and differentiat...
Interaction between adult stem cells and their progeny is critical for tissue homeostasis and regeneration. In multiple organs, mesenchymal stem cells (MSCs) give rise to transit amplifying cells (TACs), which then differentiate into different cell types. However, whether and how MSCs interact with TACs remains unknown. Using the adult mouse inciso...
Human oral soft tissues provide the first barrier of defence against chronic inflammatory disease and hold a remarkable scarless wounding phenotype. Tissue homeostasis requires coordinated actions of epithelial, mesenchymal, and immune cells. However, the extent of heterogeneity within the human oral mucosa and how tissue cell types are affected du...
The interaction between immune cells and stem cells is important during tissue repair. Macrophages have been described as being crucial for limb regeneration and in certain circumstances have been shown to affect stem cell differentiation in vivo. Dentine is susceptible to damage as a result of caries, pulp infection and inflammation all of which a...
Loss of tissue attachment as a consequence of bacterial infection and inflammation represents the main therapeutic target for the treatment of periodontitis. Cementoblasts, the cells that produce the mineralized tissue, cementum, that is responsible for connecting the soft periodontal tissue to the tooth, are a key cell type for maintaining/restori...
Understanding cell types and mechanisms of dental growth is essential for reconstruction and engineering of teeth. Therefore, we investigated cellular composition of growing and non-growing mouse and human teeth. As a result, we report an unappreciated cellular complexity of the continuously-growing mouse incisor, which suggests a coherent model of...
One of the main goals of dentistry is the natural preservation of the tooth structure following damage. This is particularly implicated in deep dental cavities affecting dentin and pulp, where odontoblast survival is jeopardized. This activates pulp stem cells and differentiation of new odontoblast-like cells, accompanied by increased Wnt signaling...
Human oral soft tissues provide the first barrier of defence against chronic inflammatory disease and hold a remarkable scarless wounding phenotype. Tissue homeostasis requires coordinated actions of epithelial, mesenchymal and immune cells. However, the extent of heterogeneity within the human oral mucosa and how tissue cell types are affected dur...
Pericytes represent a population of mesenchymal cells that are found in virtually all vascularised organs where they share a range of similar features, mostly associated with vascular maintenance roles. It is becoming increasingly apparent that organ to organ differences exist between pericytes that directly relate to tissue-specific functions of t...
BCOR is a critical regulator of human development. Heterozygous mutations of BCOR in females cause the X-linked developmental disorder Oculofaciocardiodental syndrome (OFCD), and hemizygous mutations of BCOR in males cause gestational lethality. BCOR associates with Polycomb group proteins to form one subfamily of the diverse Polycomb repressive co...
Objective
Hypohidrotic ectodermal dysplasia (HED) is a hereditary disorder characterized by abnormal structures and functions of the ectoderm‐derived organs, including teeth. HED patients exhibit a variety of dental symptoms, such as hypodontia. Although disruption of the EDA/EDAR/EDARADD/NF‐κB pathway is known to be responsible for HED, it remains...
The aim of our study was to isolate populations of keratinocyte stem cells based on the expression of cell surface markers and to investigate whether the culture could affect their phenotype. keratinocytes from human oral mucosa were sorted based on the expression of the epithelial stem cell markers p75NTR and CD71. We also examined the co-expressi...
The canonical Wnt/β-catenin signaling pathway is crucial for reparative dentinogenesis following tooth damage, and the modulation of this pathway affects the rate and extent of reparative dentine formation in damaged mice molars by triggering the natural process of dentinogenesis. Pharmacological stimulation of Wnt/β-catenin signaling activity by s...
The increasing application of approaches that allow tracing of individual cells over time, together with transcriptomics and epigenomics analyses is changing the way resident stromal stem cells (mesenchymal stem cells) are viewed. Rather than being a defined, homogeneous cell population as described following in vitro expansion, in vivo, these cell...
Dental stem cells have many applications in medicine, dentistry and stem cell biology in general due to their easy accessibility and low morbidity. A common surgical manoeuvre after a tooth extraction is the dental socket curettage which is necessary to clean the alveolus and favour alveolar bone healing. This procedure can cause very low morbidity...
Teeth might not at first seem to be an obvious organ for developing biological methods for replacement or repair. Teeth are nonessential organs, and modern dental treatments enable most dental problems to be treated using traditional nonbiological approaches. They do, however, offer unique opportunities to develop tissue-engineering-based approache...
The mandible is a crucial organ in both clinical and biological fields due to the high frequency of congenital anomalies and the significant morphological changes during evolution. Primary cilia play a critical role in many biological processes, including the determination of left/right axis patterning, the regulation of signaling pathways, and the...
In Lake Malawi cichlids, each tooth is replaced in one-for-one fashion every ∼20 to 50 d, and taste buds (TBs) are continuously renewed as in mammals. These structures are colocalized in the fish mouth and throat, from the point of initiation through adulthood. Here, we found that replacement teeth (RT) share a continuous band of epithelium with ad...
Cells have been identified in postnatal tissues that, when isolated from multiple mesenchymal compartments, can be stimulated in vitro to give rise to cells that resemble mature mesenchymal phenotypes, such as odontoblasts, osteoblasts, adipocytes, and myoblasts. This has made these adult cells, collectively called mesenchymal stem cells (MSCs), st...
Objectives:
Wnt/β-catenin signalling plays important roles in regeneration, particularly in hard tissues such as bone and teeth, and can be regulated by small molecule antagonists of glycogen synthase kinase 3 (GSK3); however, small molecules can be difficult to deliver clinically. Lithium (Li) is also a GSK3 antagonist and can be incorporated int...
The physiological role of mesenchymal stem cells (MSCs) is to provide a source of cells to replace mesenchymal-derivatives in stromal tissues with high cell turnover or following stromal tissue damage to elicit repair. Human MSCs have been shown to suppress in vitro T-cell responses via a number of mechanisms including indoleamine 2,3-dioxygenase (...
Objective:
The development of the maxillary bone is under strict molecular control because of its complicated structure. Primary cilia play a critical role in craniofacial development, since defects in primary cilia are known to cause congenital craniofacial dysmorphologies as a wide spectrum of human diseases: the ciliopathies. The primary cilia...
Background
The timing, location, and level of gene expression are crucial for normal organ development, since morphogenesis requires strict genetic control. MicroRNAs (miRNAs) are noncoding small single‐stranded RNAs that play a critical role in regulating gene expression level. Although miRNAs are known to be involved in many biological events, th...
Different animal models have been introduced recently to study the process of reparative dentinogenesis in response to injury-induced pulp exposure. Using a mouse model is advantageous over other animal models since mice can be genetically manipulated to examine specific cellular pathways and lineage trace the progeny of a single cell. However, ena...
Purpose of Review
Current dental treatments are based on conservative approaches, using inorganic materials and appliances.
This report explores and discusses the newest achievements in the field of “regenerative dentistry,” based on the concept of biological repair as an alternative to the current conservative approach.
Recent Findings
The review...
Periodic patterning of iterative structures is diverse across the animal kingdom. Clarifying the molecular mechanisms involved in the formation of these structure helps to elucidate the process of organogenesis. Turing-type reaction-diffusion mechanisms have been shown to play a critical role in regulating periodic patterning in organogenesis. Pala...
Objectives
To identify the genetic basis of severe tooth agenesis in a family of three affected sisters.
Patients and Methods
A family of three sisters with severe tooth agenesis was recruited for whole‐exome sequencing to identify potential genetic variation responsible for this penetrant phenotype. The unaffected father was tested for specific m...
Table S1. Differentially Gene Expression Profile following Ring1b Deletion, Related to Figure 3A
In adult tissues and organs with high turnover rates, the generation of transit-amplifying cell (TAC) populations from self-renewing stem cells drives cell replacement. The role of stem cells is to provide a renewable source of cells that give rise to TACs to provide the cell numbers that are necessary for cell differentiation. Regulation of the fo...
Kabuki syndrome is a rare genetic disorder characterized by distinct dysmorphic facial features, intellectual disability, and multiple developmental abnormalities. Despite more than 350 documented cases, the oro-dental spectrum associated with kabuki syndrome and expression of KMT2D (histone-lysine N-methyltransferase 2D) or KDM6A (lysine-specific...
Mesenchymal stem cells (MSCs) show considerable promise as a cellular immunotherapy for the treatment of a number of autoimmune and inflammatory disorders. However, the precise physiologically and therapeutically relevant mechanism(s) by which MSCs mediate immune modulation remains elusive. Dental pulp stem cells are a readily available source of M...
The extent to which heterogeneity within mesenchymal stem cell (MSC) populations is related to function is not understood. Using the archetypal MSC in vitro surface marker, CD90/Thy1, here we show that 30% of the MSCs in the continuously growing mouse incisor express CD90/Thy1 and these cells give rise to 30% of the differentiated cell progeny duri...
During the treatment of dental caries that has not penetrated the tooth pulp, maintenance of as much unaffected dentine as possible is a major goal during the physical removal of decayed mineral. Damage to dentine leads to release of fossilized factors (transforming growth factor–β [TGF-β] and bone morphogenic protein [BMP]) in the dentine that are...
Bioactive glasses (BG) are used clinically because they can both bond to hard tissue and release therapeutic ions that can stimulate nearby cells. Lithium has been shown to regulate the Wnt/β-catenin cell signalling pathway, which plays important roles in the formation and repair of bone and teeth. Lithium-releasing BG, therefore, have the potentia...
In non-growing teeth, such as mouse and human molars, primary odontoblasts are long-lived post-mitotic cells that secrete dentine throughout the life of the tooth. New odontoblast-like cells are only produced in response to a damage or trauma. Little is known about the molecular events that initiate mesenchymal stem cells to proliferate and differe...
Objective:
Inherited congenital anomalies in tooth number, particularly hypodontia are relatively common. Although substantial progress has been made that permits a better understanding of the causes of tooth agenesis, overall knowledge of the phenotype:genotype correlations in this anomaly are still lacking. The aim in this study was to identify...
The restoration of dentine lost in deep caries lesions in teeth is a routine and common treatment that involves the use of inorganic cements based on calcium or silicon-based mineral aggregates. Such cements remain in the tooth and fail to degrade and thus normal mineral volume is never completely restored. Here we describe a novel, biological appr...
In vitro expanded cell populations can contribute to bioengineered tooth formation but only as cells that respond to tooth-inductive signals. Since the success of whole tooth bioengineering is predicated on the availability of large numbers of cells, in vitro cell expansion of tooth-inducing cell populations is an essential requirement for further...
Cranial neural crest cells populate the future facial region and produce ectomesenchyme-derived tissues, such as cartilage, bone, dermis, smooth muscle, adipocytes, and many others. However, the contribution of individual neural crest cells to certain facial locations and the general spatial clonal organization of the ectomesenchyme have not been d...