Keloid disorder, a recently coined term, refers to a group of fibroproliferative disorders affecting the skin (Tirgan, 2019aTirgan M.H. Clinical presentation and overview of keloid disorder.Int J Keloid Res. 2019; 3: 6Google Scholar). The clinical spectrum of such conditions includes keloids and hypertrophic scars, as well as acne keloidalis and keloidalis nuchae, in which cutaneous nodules and tumors develop as a result of trauma and inflammation (Figure 1). Keloids are relatively common, particularly affecting certain ethnic groups. Individuals of African ancestry have a very high incidence of keloids, reported to affect 4–16% of people in such populations, about 15 times higher than in individuals of European ancestry (Brown et al., 2008Brown J.J. Ollier W. Arscott G. Ke X. Lamb J. Day P. et al.Genetic susceptibility to keloid scarring: SMAD gene SNP frequencies in Afro-Caribbeans.Exp Dermatol. 2008; 17: 610-613Crossref PubMed Scopus (41) Google Scholar, Kouotou et al., 2019Kouotou E.A. Nansseu J.R. Omona Guissana E. Mendouga Menye C.R. Akpadjan F. Tounkara T.M. et al.Epidemiology and clinical features of keloids in Black Africans: a nested case-control study from Yaounde, Cameroon.Int J Dermatol. 2019; 58: 1135-1140Crossref PubMed Scopus (6) Google Scholar). Also, the individuals with Asian ancestral background have a high propensity for development of keloids (Lu et al., 2015Lu W.S. Zheng X.D. Yao X.H. Zhang L.F. Clinical and epidemiological analysis of keloids in Chinese patients.Arch Dermatol Res. 2015; 307: 109-114Crossref PubMed Scopus (25) Google Scholar). Thus, keloid disorder comprises a prevalent group of debilitating skin conditions with high degree of morbidity (Karppinen et al., 2019Karppinen S.M. Heljasvaara R. Gullberg D. Tasanen K. Pihlajaniemi T. Toward understanding scarless skin wound healing and pathological scarring.. 2019; 8: F1000ResGoogle Scholar, Lyons et al., 2019Lyons A.B. Peacock A. Braunberger T.L. Viola K.V. Ozog D.M. Disease severity and quality of life outcome measurements in patients with keloids: A systematic review.Dermatol Surg. 2019; 45: 1477-1483Crossref PubMed Scopus (4) Google Scholar). Besides aesthetic impact, the lesions are often pruritic and prone to infections, impairing the quality of life of the affected individuals, with no effective and specific treatment currently available. The Keloid Research Foundation (KRF), a professional nonprofit organization advocating on behalf of patients and families with keloids, was established in 2011 with the goal to raise awareness of keloids and to develop improved treatments. Toward this aim, KRF organizes an annual clinical and research symposium revolving around keloid disorder. The latest KRF meeting was held in Beijing April 19–21, 2019, with 39 speakers and well over 120 participants (Figure 2). This Report summarizes the current understanding of the pathomechanisms of keloid lesions and highlights the need for additional research toward development of effective treatments, based on presentations and discussions in the Beijing 2019 meeting. The abstracts on presentations in this meeting can be found in the Journal of Keloid Research, Vol. 3, No. 1 (April 15, 2019). Histopathologic examination of keloid lesions has demonstrated accumulation of extracellular matrix (ECM) of connective tissue, with compact packing of collagen fibers (Figure 1). Embedded into the connective tissue matrix are variable numbers of cells, often with fibroblastic appearance with evidence of myofibroblastic differentiation, attested to by expression of α-smooth muscle actin and vimentin (Figure 3). Besides myofibroblasts, there are myofibroblast-like subpopulations with a lesser degree of differentiation reflecting the heterogeneity of the phenotypic features of myofibroblasts and attesting to the fibroblastic cell plasticity. In addition, mast cells are abundantly present in keloids, often in close association with myofibroblasts with direct cell-cell contacts leading to profibrotic responses (Arbi et al., 2015Arbi S. Eksteen E.C. Oberholzer H.M. Taute H. Bester M.J. Premature collagen fibril formation, fibroblast-mast cell interactions and mast cell-mediated phagocytosis of collagen in keloids.Ultrastruct Pathol. 2015; 39: 95-103Crossref PubMed Scopus (14) Google Scholar, Dong et al., 2014Dong X. Zhang C. Ma S. Wen H. Mast cell chymase in keloid induces profibrotic response via transforming growth factor-beta1/Smad activation in keloid fibroblasts.Int J Clin Exp Pathol. 2014; 7: 3596-3607PubMed Google Scholar, Pistorio and Ehrlich, 2011Pistorio A.L. Ehrlich H.P. Modulatory effects of connexin-43 expression on gap junction intercellular communications with mast cells and fibroblasts.J Cell Biochem. 2011; 112: 1441-1449Crossref PubMed Scopus (34) Google Scholar). In addition, there is increasing evidence for the role of stem cells in keloid lesions, and it has been proposed that stem cell populations localized to the endothelium of the microvessels may give rise to aberrant fibroblasts and myofibroblasts via a mesenchymal stem cell intermediate by undergoing an endothelial-to-mesenchymal transition (Lim et al., 2019Lim K.H. Itinteang T. Davis P.F. Tan S.T. Stem cells in keloid lesions: a review.Plast Reconstr Surg Glob Open. 2019; 7: e2228Crossref PubMed Scopus (9) Google Scholar, Yuan et al., 2019Yuan F.L. Sun Z.L. Feng Y. Liu S.Y. Du Y. Yu S. et al.Epithelial-mesenchymal transition in the formation of hypertrophic scars and keloids.J Cell Physiol. 2019; 234: 21662-21669Crossref PubMed Scopus (16) Google Scholar). Thus, there is a considerable heterogeneity of cell populations, with diverse biosynthetic profiles within keloids. In addition to overexpression of collagen, of particular interest is the expression of a specific fibronectin splice variant, cFN-EDA. Fibronectin is a high molecular weight glycoprotein, and the single copy human FN gene consists of 45 exons, which can be alternatively spliced from pre-mRNA, resulting in as many as 20 different mRNA variants (Schwarzbauer et al., 1987Schwarzbauer J.E. Patel R.S. Fonda D. Hynes R.O. Multiple sites of alternative splicing of the rat fibronectin gene transcript.EMBO J. 1987; 6: 2573-2580Crossref PubMed Scopus (235) Google Scholar). The fibronectin isoforms then interact with matrix proteins, such as collagens, glycosaminoglycans, and fibrin, as well as a number of cell surface receptors, including several integrins and toll-like receptor 4 (Kelsh-Lasher et al., 2017Kelsh-Lasher R.M. Ambesi A. Bertram C. McKeown-Longo P.J. Integrin alpha4beta1 and TLR4 cooperate to induce fibrotic gene expression in response to fibronectin's EDA domain.J Invest Dermatol. 2017; 137: 2505-2512Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, Singh et al., 2010Singh P. Carraher C. Schwarzbauer J.E. Assembly of fibronectin extracellular matrix.Annu Rev Cell Dev Biol. 2010; 26: 397-419Crossref PubMed Scopus (534) Google Scholar). A distinct fibronectin variant contains an extra domain that is present exclusively in the cellular fibronectin and is produced by a variety of cells, including fibroblasts and epithelial cells, and then deposited in the ECM. Recently, significant evidence has accumulated implicating cFN-EDA not only in wound healing but also in fibroproliferative disorders. Specifically, such studies have suggested that cFN-EDA stimulates collagen production and myofibroblast differentiation in vitro mediated by toll-like receptor 4 (Bhattacharyya et al., 2014Bhattacharyya S. Tamaki Z. Wang W. Hinchcliff M. Hoover P. Getsios S. et al.Fibronectin EDA promotes chronic cutaneous fibrosis through toll-like receptor signaling.Sci Transl Med. 2014; 6: 232ra50Crossref PubMed Scopus (134) Google Scholar). In keloids, the cFN-EDA expression is dramatically upregulated, up to 70-fold (Andrews et al., 2015Andrews J.P. Marttala J. Macarak E. Rosenbloom J. Uitto J. Keloid pathogenesis: potential role of cellular fibronectin with the EDA domain.J Invest Dermatol. 2015; 135: 1921-1924Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). In addition, the cFN-EDA levels are increased in a number of other fibrotic conditions, suggesting that despite striking phenotypic differences between these conditions, cFN-EDA/toll-like receptor 4 interaction-dependent pathways may be the unifying feature in fibrotic diseases (Kelsh et al., 2015Kelsh R.M. McKeown-Longo P.J. Clark R.A.F. EDA fibronectin in keloids create a vicious cycle of fibrotic tumor formation.J Invest Dermatol. 2015; 135: 1714-1718Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar). In most cases, tissue fibrosis is a reactive process and a number of factors can modulate the pathways leading to collagen accumulation and tissue fibrosis (Figure 3). Such factors include the local expansion of resident fibroblast subpopulations, immune modulation of the synthetic functions of fibroblasts and myofibroblasts, and altered regulation of various metabolic reactions governing the biosynthesis and degradation of the connective tissue components, as well as altered keratinocyte-fibroblast interactions (Marneros and Krieg, 2004Marneros A.G. Krieg T. Keloids--clinical diagnosis, pathogenesis, and treatment options.J Dtsch Dermatol Ges. 2004; 2: 905-913Crossref PubMed Scopus (106) Google Scholar). One such growth factor is transforming growth factor-β, which has been demonstrated to be abundantly present in keloids. Thus, inhibition of transforming growth factor-β activity by small molecular weight compounds or peptide inhibitors is currently being pursued toward development of treatment of fibrotic diseases. In addition to immune modulation, other factors, such as epigenetics, have been suggested to play a role in persistent activation of keloid fibroblasts. These include modulation by noncoding RNAs (microRNAs and long noncoding RNAs) as well as DNA methylation (Tsai and Ogawa, 2019Tsai C.H. Ogawa R. Keloid research: current status and future directions.Scars Burn Heal. 2019; 5 (2059513119868659)PubMed Google Scholar, Wang et al., 2019aWang R. Bai Z. Wen X. Du H. Zhou L. Tang Z. et al.MiR-152-3p regulates cell proliferation, invasion and extracellular matrix expression through by targeting FOXF1 in keloid fibroblasts.Life Sci. 2019; 234: 116779Crossref PubMed Scopus (16) Google Scholar, Wu et al., 2019Wu J. Fang L. Cen Y. Qing Y. Chen J. Li Z. MiR-21 regulates keloid formation by downregulating Smad7 via the TGF-beta/Smad signaling pathway.J Burn Care Res. 2019; 40: 809-817Crossref PubMed Scopus (8) Google Scholar, Xu et al., 2019Xu Z. Guo B. Chang P. Hui Q. Li W. Tao K. The differential expression of miRNAs and a preliminary study on the mechanism of miR-194-3p in keloids.BioMed Res Int. 2019; 2019: 8214923PubMed Google Scholar). These observations may provide new targets for controlling ECM production in keloids. There is no spontaneous animal model for keloids, and the model systems utilized for in vivo studies of fibrotic diseases, such as bleomycin-induced fibrosis, do not recapitulate the features of keloids (Marttala et al., 2016Marttala J. Andrews J.P. Rosenbloom J. Uitto J. Keloids: animal models and pathologic equivalents to study tissue fibrosis.Matrix Biol. 2016; 51: 47-54Crossref PubMed Scopus (31) Google Scholar). Thus, the bulk of information on keloids has been derived from in vitro studies routinely culturing fibroblasts on tissue culture plastic. Such studies have demonstrated that activation of collagen gene expression in keloid fibroblasts in primary cultures takes place at pretranslational level, but the collagen-overexpressing phenotype returns to normal within a few passages when the cells are cultured on a plastic surface that does not mimic the in vivo physicochemical properties of skin tissue. In fact, the stiffness of a petri dish (109 Pa) far exceeds the stiffness encountered in normal skin (1–5 × 103 Pa) (Pailler-Mattei et al., 2008Pailler-Mattei C. Bec S. Zahouani H. In vivo measurements of the elastic mechanical properties of human skin by indentation tests.Med Eng Phys. 2008; 30: 599-606Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar). A study reported in this meeting examined the impact of matrix stiffness on fibroblast phenotypes by culturing cells on surfaces of varying degrees of stiffness (Deng et al., 2019Deng Z. Subilia M. Choi Y.S. Hortin N. Stevenson A. Wood F. et al.The impact of matrix stiffness on fibroblast phenotype and keloid.Int J Keloid Res. 2019; 3: 15Google Scholar). The results demonstrated that the expression of α-smooth muscle actin was increased with increasing matrix stiffness in both normal and keloid fibroblasts. This was accompanied by nuclear translocation of YAP, a key mechano-activated coordinator of fibroblast activation and matrix deposition. These and other observations resulted in the conclusion that normal skin fibroblasts respond to the physical properties of the matrix in vitro, but keloid fibroblasts appear to have elevated activation of mechanotransduction pathways irrespective of the environment (Deng et al., 2019Deng Z. Subilia M. Choi Y.S. Hortin N. Stevenson A. Wood F. et al.The impact of matrix stiffness on fibroblast phenotype and keloid.Int J Keloid Res. 2019; 3: 15Google Scholar). Another mechanism for activation of collagen gene expression in keloid cells explored the effect of cellular stretching on the ECM gene expression profile in keloid cells (Wang et al., 2019bWang S. Macarak E. Yang J. Rosenbloom J. Uitto J. Extracellular matrix gene expression profile in keloid fibroblasts: the effects of cellular stretching.Int J Keloid Res. 2019; 3: 22-23Google Scholar). Fibroblasts derived from keloid tissue and normal skin stretched by a bi-axial strain of 10% at a frequency of 1 Hz demonstrated marked increases in mRNA transcript levels in keloid fibroblasts, particularly showing elevated mRNA for total fibronectin and cFN-EDA. Furthermore, activation of the gene expression in many cases was significantly higher upon stretching of keloid fibroblasts as compared with control cells. The cellular topography as a modifying factor of cell behavior was further investigated in a study were keloid fibroblasts were cultured on a surface with parallel microgrooves (Huang, 2019Huang J. Aligned topography mediated cell elongation reverses pathological phenotype of vitro cultured keloid fibroblasts.Int J Keloid Res. 2019; 3: 10Google Scholar). In particular, growing cells in grooves with 3-μm depth and 10-μm width resulted in significant elongation and alignment of the cultured cells with reduced nuclear area. The elongated cells gradually lost their fibrotic phenotype with reduced cell proliferation and cell cycle arrest in S-phase. These changes were accompanied with reduced expression of fibrotic markers, such as collagen, fibronectin, α-smooth muscle actin and transforming growth factor-β1, along with attenuated SMAD and extracellular signal-regulated kinase phosphorylation levels (Huang, 2019Huang J. Aligned topography mediated cell elongation reverses pathological phenotype of vitro cultured keloid fibroblasts.Int J Keloid Res. 2019; 3: 10Google Scholar). Collectively, these studies demonstrated that expression of certain ECM genes is activated in situ in cultured keloid fibroblasts as compared with controls, and such changes are markedly accentuated by altering the topography by stretching of the cells or changing the stiffness of the growth matrix. These observations emphasize the role of the extracellular milieu and cell microenvironment in selectively controlling the gene expression profile and as a contributor to keloid formation (Dohi et al., 2019Dohi T. Padmanabhan J. Akaishi S. Than P.A. Terashima M. Matsumoto N.N. et al.The interplay of mechanical stress, strain, and stiffness at the keloid periphery correlates with increased caveolin-1/ROCK signaling and scar progression.Plast Reconstr Surg. 2019; 144: 58e-67eCrossref PubMed Scopus (15) Google Scholar). Despite increasing knowledge of the pathomechanisms of fibrotic diseases, there is no uniformly effective treatment, and a myriad of approaches have been reported, with variable success (González and Goldberg, 2019González N. Goldberg D.J. Update on the treatment of scars.J Drugs Dermatol. 2019; 18: 550PubMed Google Scholar). Monotherapy with a variety of approaches, including surgical excision, intralesional steroid injections, brachytherapy, and silicone sheath application, has resulted in a high degree of recurrence (Tirgan, 2019bTirgan M.H. KRF clinical practice guidelines - treatment strategy.Int J Keloid Res. 2019; 3: 12-13Google Scholar). In addition, some of these treatment modalities, such as radiation therapy and/or frequent injections of high-dose intralesional steroids, are known to result in long-term adverse effects. It appears that the biggest obstacle to development of optimal treatment of patients with keloids is the lack of data-driven treatment pathways, and there is a paucity of properly designed and well-conducted clinical trials that would form the foundation for proper clinical management of patients with different types of keloids. The current treatment guidance, as recommended by KRF, is based on the following methods of treatment: (i) intralesional trimcinolone, (ii) intralesional chemotherapy, (iii) contact cryotherapy, and (iv) pressure devices (Tirgan, 2019bTirgan M.H. KRF clinical practice guidelines - treatment strategy.Int J Keloid Res. 2019; 3: 12-13Google Scholar). At this time, KRF advises against surgery, radiation therapy, and laser treatment, particularly as monotherapies. KRF’s recommendations are for the most part based on efforts to reduce the risk for the iatrogenic worsening of the keloids. It is obvious that an optimal way to treat keloids would be a nonsurgical intervention at the very early stages of keloid lesions which all start as a small papule or a minor linear lesion. This should be done as soon as the diagnosis is made, before the lesions demonstrate aggressive growth. Increased knowledge of the pathogenic mechanisms and detailed information on the contributing factors are critical for development of rational, targeted therapy for keloids. Along these lines, topical lysyl oxidase inhibitors, transforming growth factor-β antagonists, dual inhibition of PI3K/Akt/mTOR signaling, and histone deacetylase 2 serve as examples of the approaches that are currently being tested in preclinical studies. Furthermore, development of improved technologies of surgery, radiotherapy, and laser therapy, when combined with targeted therapies under development, might provide a multifaceted approach to treat keloids in the future as discussed in the Symposium (see Proceedings of the Symposium: J. Keloid Res, 3(1), 2019). Although reported in individuals from almost all ethnic backgrounds, keloid disorder is more common among two distinct and genetically distant populations, those of African and Asian ancestry. It is clear that much more research is needed to determine the pathomechanisms and the genetic underpinnings of keloids. Lack of progress in keloid disorder is in part caused by lack of lobbying groups for this condition. Although quite common, keloid disorder has not captured the interest of research community commensurate with its impact on individuals and its overall prevalence in certain ethnic groups. This Third KRF International Keloid Symposium in Beijing 2019 was a clarion call for further research, with increased support from National Institutes of Health in the United States and its international counterparts as well as from other funding agencies, so as to facilitate development of approaches for prevention and treatment of this devastating condition with suboptimal treatment options currently available.