Ardeshir Bayat

Current understanding of molecular and cellular mechanisms in fibroplasia and angiogenesis during acute wound healing

Cutaneous wound healing ultimately functions to facilitate barrier restoration following injury-induced loss of skin integrity. It is an evolutionarily conserved, multi-cellular, multi-molecular process involving co-ordinated inter-play between complex signalling networks. Cellular proliferation is recognised as the third stage of this sequence. Within this phase, fibroplasia and angiogenesis are co-dependent processes which must be successfully completed in order to form an evolving extracellular matrix and granulation tissue. The resultant structures guide cellular infiltration, differentiation and secretory profile within the wound environment and consequently have major influence on the success or failure of wound healing. This review integrates in vitro, animal and human in vivo studies, to provide up to date descriptions of molecular and cellular interactions involved in fibroplasia and angiogenesis. Significant molecular networks include adhesion molecules, proteinases, cytokines and chemokines as well as a plethora of growth factors. These signals are produced by, and affect behaviour of, cells including fibroblasts, fibrocytes, keratinocytes, endothelial cells and inflammatory cells resulting in significant cellular phenotypic and functional plasticity, as well as controlling composition and remodelling of structural proteins including collagen and fibronectin. The interdependent relationship between angiogenesis and fibroplasia relies on dynamic reciprocity between cellular components, matrix proteins and bioactive molecules. Unbalanced regulation of any one component can have significant consequences resulting in delayed healing, chronic wounds or abnormal scar formation. Greater understanding of angiogenic and fibroplastic mechanisms underlying chronic wound pathogenesis has identified novel therapeutic targets and enabled development of improved treatment strategies including topical growth factors and skin substitutes.

Exploring the role of stem cells in cutaneous wound healing

Abstract:  The skin offers a perfect model system for studying the wound healing cascade, which involves a finely tuned interplay between several cell types, pathways and processes. The dysregulation of these factors may lead to wound healing disorders resulting in chronic wounds, as well as abnormal scars such as hypertrophic and keloid scars. As the contribution of stem cells towards tissue regeneration and wound healing is increasingly appreciated, a rising number of stem cell therapies for cutaneous wounds are currently under development, encouraged by emerging preliminary findings in both animal models and human studies. However, we still lack an in‐depth understanding of the underlying mechanisms through which stem cells contribute to cutaneous wound healing. The aim of this review is, therefore, to present a critical synthesis of our current understanding of the role of stem cells in normal cutaneous wound healing. In addition to summarizing wound healing principles and related key molecular and cellular players, we discuss the potential participation of different cutaneous stem cell populations in wound healing, and list corresponding stem cells markers. In summary, this review delineates current strategies, future applications, and limitations of stem cell‐based or stem cell‐targeted therapy in the management of acute and chronic skin wounds.

Molecular dissection of abnormal wound healing processes resulting in keloid disease

Keloids are locally aggressive scars that typically invade into healthy surrounding skin and cause both physical and psychosocial distress to the patient. These pathological scars occur following minimal skin trauma after a variety of causes including burns and trauma. Although the pathogenesis of keloid disease is not well understood, it is considered to be the end product of an abnormal healing process. The aim of this review was to investigate the molecular and cellular pathobiology of keloid disease in relation to the normal wound healing process. The molecular aberrances in keloids that correlate with the molecular mechanisms in normal wound healing can be categorized into three groups: (1) extracellular matrix proteins and their degradation, (2) cytokines and growth factors, and (3) apoptotic pathways. With respect to cellular involvements, fibroblasts are the most well‐studied cell population. However, it is unclear whether the fibroblast is the causative cell; they are modulated by other cell populations in wound repair, such as keratinocytes and macrophages. This review presents a detailed account of individual phases of the healing process and how they may potentially be implicated in aberrant raised scar formation, which may help in clarifying the mechanisms involved in keloid disease pathogenesis.

Genetics of keloid scarring.

Keloid scarring, also known as keloid disease (KD), is a common, abnormally raised fibroproliferative cutaneous lesion that can occur following even minor skin trauma. The aetiopathogenesis of KD has remained an enigma todate compounded by an ill-defined clinical management. There is strong evidence suggesting a genetic susceptibility in individuals affected by KD, including familial heritability, common occurrence in twins and high prevalence in certain ethnic populations. This review aims to address the genetic aspects of KD that have been described in present literature that include inheritance patterns, linkage studies, case–control association studies, whole genome gene expression microarray studies and gene pathways that were significant in KD. In addition to our clinical and scientific background in KD, we used search engines, Scopus, Scirus and PubMed, which searched for key terms covering various genetic aspects of KD. Additionally, genes reported in seven whole genome gene expression microarray studies were separately compared in detail. Our findings indicate a varied inheritance pattern in KD (predominantly autosomal dominant), linkage loci (chromosomes 2q23 and 7p11), several human leukocyte antigen (HLA) alleles (HLA-DRB1*15, HLA-DQA1*0104, DQ-B1*0501 and DQB1*0503), negative candidate gene case–control association studies and at least 25 dysregulated genes reported in multiple microarray studies. The major pathways reportedly proposed to be involved in KD include apoptosis, mitogen-activated protein kinase, transforming growth factor-β, interleukin-6 and plasminogen activator inhibitor-1. In summary, involvement of more than one gene is likely to be responsible for susceptibility to KD. A better understanding of the genes involved in KD may potentially lead to the development of more effective diagnostic, therapeutic and prognostic measures.

Epidemiological evaluation of Dupuytren's disease incidence and prevalence rates in relation to etiology.

Dupuytren’s Disease (DD) is a common, fibroproliferative disorder affecting the palmar surface of the hands which is often irreversible and progressive. Understanding the epidemiology of DD is important in order to provide clues to its etiopathogenesis. This review aims to evaluate the epidemiological studies carried out in DD since 1951. Studies evaluating the epidemiology of DD were searched using Medline, Pubmed, and Scopus which dated back from 1951 to current date. Inclusion criteria were any studies investigating the prevalence or incidence of DD in any population group. A total of 620 articles were cited. Forty-nine studies were subsequently identified as relevant to evaluating the epidemiology of DD. The prevalence of DD in all studies increased with age with a male to female ratio of approximately 5.9:1. Prevalence rates ranged from 0.2% to 56% in varying age, population groups, and methods of data collection. The highest prevalence rate was reported in a study group of epileptic patients. Although, only one study calculated the incidence (as opposed to prevalence) of DD to be equal to 34.3 per 100,000 men (0.03%). In conclusion, the prevalence of DD in different geographical locations is extremely variable, and it is not clear whether this is genetic, environmental, or a combination of both. The majority of the prevalence studies have been conducted in Scandinavia or the UK, and the vast changes in population structure, the changes in prevalence of associated diseases, and the change in diagnostic criteria of DD makes understanding the epidemiology of this condition difficult.

Genetic susceptibility to raised dermal scarring

Raised skin scars, such as keloid and hypertrophic scars mostly occur post‐wounding in the human dermis. There is compelling evidence for a genetic component to these conditions, given the familial predisposition, varied incidence in different ethnic populations and the presence in twins. The aim of this study was to perform a systematic review of the literature regarding genetic susceptibility to raised dermal scarring. We identified relevant articles by a systematic search of relevant search engines. Key search terms included: keloid disease, hypertrophic scarring, fibrosis, linkage analysis, gene expression, human leucocyte antigen system (HLA), twins, families, case–control association study and congenital syndromes. Numerous candidate genes have been identified, along with potential linkage regions on different chromosomes. Recent data also suggest that carriers of specific major histocompatibility complex (MHC) alleles, in particular HLA‐DRB1*15, HLA‐DQA1*0104, DQB1*0501 and DQB1*0503, are at increased risk of developing keloid scarring. In addition, distinct immunophenotypical profiles can distinguish between keloid and hypertrophic scars. Keloid and hypertrophic scars are multifaceted aberrations of the healing process with as yet incompletely understood aetiologies. Current data suggest a genetic susceptibility with a strong immunogenic component to dermal fibrosis with MHC genes being implicated. It appears unlikely that a single gene is responsible for the development of raised dermal scars. A likely scenario may involve the interaction of several gene pathways in addition to environmental factors. The ability to assess accurately an individual’s potential genetic susceptibility to raised scarring may lead to a more personalized approach to their management in the future.

Scientific understanding and clinical management of Dupuytren disease

Dupuytren disease (DD) is a fibroproliferative disorder of unknown etiology that often results in shortening and thickening of the palmar fascia, leading to permanent and irreversible flexion contracture of the digits. This Review provides a detailed update of the scientific understanding of DD and its clinical management, with perspectives on emerging research and therapy. Established risk factors include genetic predisposition and ethnicity, as well as sex and age. Several environmental risk factors (some considered controversial) include smoking, alcohol intake, trauma, diabetes, epilepsy and use of anticonvulsant drugs, and exposure to vibration. DD has been variously attributed to the presence of oxygen free radicals, trauma to the palmar fascia, or aberrant immune responses with altered antigen presentation, or to interactions between these proposed mechanisms. The presence of immune cells and related phenomena in DD-affected tissue suggests that DD is possibly immune-related. Mechanically, digital contracture is caused by myofibroblasts in the DD palmar fascia; however, the exact origin of this cell type remains unknown. The mainstay of treatment is surgical release or excision of the affected palmodigital tissue, but symptoms often recur. Nonsurgical correction of DD contractures can be achieved by Clostridium histolyticum collagenase injection, although the long-term safety and recurrence rate of this procedure requires further assessment.

Fibroblasts from the growing margin of keloid scars produce higher levels of collagen I and III compared with intralesional and extralesional sites: clinical implications for lesional site-directed therapy.

Background  Overproduction of collagen and its abnormal assembly are hallmarks of keloid scars. Type I/III collagen ratios are altered in keloids compared with normal skin. Fibroblasts from different sites in keloid tissue, perilesional compared with intralesional and extralesional sites, show differential apoptosis and contraction. Additionally, early vs. later cell culture passages display differential collagen expression. We therefore hypothesize that keloid fibroblasts from the growing margin of the keloid express higher levels of collagen type I and III, and that collagen production is altered by extended cell culture passage.

Management of Dupuytren's Disease – Clear Advice for an Elusive Condition

Dupuytrens disease is a progressive fibroproliferative disorder of an unknown origin affecting the hands causing permanent flexion contracture of the digits. Significant risk factors for development of Dupuytrens disease include old age, male sex, white northern European extraction, presence of positive family history of Dupuytrens disease, and diabetes mellitus. The disease also seems to deteriorate rapidly in those cases showing young age of onset and additional fibromatosis affecting the back of the hands, soles of the feet and the penis. Although there is no cure, patients with Dupuytrens disease of the hand may gain a significant functional benefit following surgical improvement or correction of the deformity. With realistic expectations, timely and appropriate surgical technique in a specialist centre, and attention to postoperative recovery and rehabilitation (occupational therapy and physiotherapy support), a beneficial outcome can be achieved in most cases.

Extracellular matrix molecules implicated in hypertrophic and keloid scarring

Tissue regeneration repairs the fabric of the skin to maintain homeostasis after injury. The expression and proliferation of extracellular matrix (ECM) molecules in the dermis, mediated by a range of growth factors and cytokines, is a fundamental element of wound repair. Previous work focused on how these complex molecular mechanisms relate to the formation of raised dermal scars, including keloid and hypertrophic scars, characterized by excessive deposition of ECM molecules. However, the mechanisms in the wound repair pathway which lead to the differential expression and organization of ECM molecules observed in different types of scar tissue are not fully understood. To summarize what is known about the expression and composition of ECM molecules in abnormal scarring, an extensive search of the literature was conducted, focusing on keywords connected to skin scarring, hypertrophic scars and keloid disease. The transcription and translation of collagen I and III, fibronectin, laminin, periostin and tenascin are all increased in raised dermal scar tissue. However, hyaluronic acid, dermatopontin and decorin are decreased, and the expression and localisation of fibrillin and elastin fibres in the dermis are altered compared with normal skin and scars. Recent whole genome profiling and proteomic studies have led to the identification of regulatory elements with different expression profiles in hypertrophic and keloid tissue. If the mechanisms of raised dermal scar formation are to be elucidated and effective therapeutic treatments developed, an integrated approach to research is required, focussing on the interactions between ECM molecules, regulatory elements and pathways.