Scar formation is characterized by dynamic alterations in collagen secretion, which critically determine scar morphology and pathological progression. In fibroblasts, collagen secretion is initiated through the activation of cytokine- and integrin-mediated signaling pathways, which promote collagen gene transcription. The procollagen polypeptide α chains undergo extensive post-translational modifications, including hydroxylation and glycosylation, within the endoplasmic reticulum (ER), followed by folding and assembly into triple-helical procollagen. Subsequent intracellular trafficking involves the sequential transport of procollagen through the ER, Golgi apparatus, and plasma membrane, accompanied by further structural refinements prior to extracellular secretion. Once secreted, procollagen is enzymatically processed to form mature collagen fibrils, which drive scar tissue remodeling. Recent advances in elucidating regulation of collagen secretion have identified pivotal molecular targets, such as transforming growth factor-beta 1 (TGF-β1), prolyl 4-hydroxylase (P4H), heat shock protein 47 (HSP47), and transport and Golgi organization protein 1 (TANGO1), providing novel therapeutic strategies to mitigate pathological scar hyperplasia and improve regenerative outcomes. This review provides a comprehensive analysis of the molecular mechanisms governing collagen secretion during scar formation, with emphasis on signaling cascades, procollagen biosynthesis, intracellular transport dynamics, and post-translational modifications, thereby offering a framework for developing targeted anti-scar therapies.
Humans ; Collagen/metabolism* ; Cicatrix/pathology* ; Signal Transduction ; Transforming Growth Factor beta1/metabolism* ; Fibroblasts/metabolism* ; Animals

Frostbite is the most common cold injury and is caused by both immediate cold-induced cell death and the gradual development of localized inflammation and tissue ischemia. Delayed healing of frostbite often leads to scar formation, which not only causes psychological distress but also tends to result in the development of secondary malignant tumors. Therefore, a rapid healing method for frostbite wounds is urgently needed. Herein, we used a mouse skin model of frostbite injury to evaluate the recovery process after frostbite. Moreover, single-cell transcriptomics was used to determine the patterns of changes in monocytes, macrophages, epidermal cells, and fibroblasts during frostbite. Most importantly, human-induced pluripotent stem cell (hiPSC)-derived skin organoids combined with gelatin-hydrogel were constructed for the treatment of frostbite. The results showed that skin organoid treatment significantly accelerated wound healing by reducing early inflammation after frostbite and increasing the proportions of epidermal stem cells. Moreover, in the later stage of wound healing, skin organoids reduced the overall proportions of fibroblasts, significantly reduced fibroblast-to-myofibroblast transition by regulating the integrin α5β1-FAK pathway, and remodeled the extracellular matrix (ECM) through degradation and reassembly mechanisms, facilitating the restoration of physiological ECM and reducing the abundance of ECM associated with abnormal scar formation. These results highlight the potential application of organoids for promoting the reversal of frostbite-related injury and the recovery of skin functions. This study provides a new therapeutic alternative for patients suffering from disfigurement and skin dysfunction caused by frostbite.
Animals ; Organoids/metabolism* ; Mice ; Humans ; Wound Healing ; Frostbite/metabolism* ; Skin/pathology* ; Induced Pluripotent Stem Cells/cytology* ; Cicatrix/pathology* ; Fibroblasts/metabolism* ; Disease Models, Animal ; Mice, Inbred C57BL ; Extracellular Matrix/metabolism* ; Male

Nerve regeneration in adult mammalian spinal cord is poor because of the lack of intrinsic regeneration of neurons and extrinsic factors - the glial scar is triggered by injury and inhibits or promotes regeneration. Recent technological advances in spatial transcriptomics (ST) provide a unique opportunity to decipher most genes systematically throughout scar formation, which remains poorly understood. Here, we first constructed the tissue-wide gene expression patterns of mouse spinal cords over the course of scar formation using ST after spinal cord injury from 32 samples. Locally, we profiled gene expression gradients from the leading edge to the core of the scar areas to further understand the scar microenvironment, such as neurotransmitter disorders, activation of the pro-inflammatory response, neurotoxic saturated lipids, angiogenesis, obstructed axon extension, and extracellular structure re-organization. In addition, we described 21 cell transcriptional states during scar formation and delineated the origins, functional diversity, and possible trajectories of subpopulations of fibroblasts, glia, and immune cells. Specifically, we found some regulators in special cell types, such as Thbs1 and Col1a2 in macrophages, CD36 and Postn in fibroblasts, Plxnb2 and Nxpe3 in microglia, Clu in astrocytes, and CD74 in oligodendrocytes. Furthermore, salvianolic acid B, a blood-brain barrier permeation and CD36 inhibitor, was administered after surgery and found to remedy fibrosis. Subsequently, we described the extent of the scar boundary and profiled the bidirectional ligand-receptor interactions at the neighboring cluster boundary, contributing to maintain scar architecture during gliosis and fibrosis, and found that GPR37L1_PSAP, and GPR37_PSAP were the most significant gene-pairs among microglia, fibroblasts, and astrocytes. Last, we quantified the fraction of scar-resident cells and proposed four possible phases of scar formation: macrophage infiltration, proliferation and differentiation of scar-resident cells, scar emergence, and scar stationary. Together, these profiles delineated the spatial heterogeneity of the scar, confirmed the previous concepts about scar architecture, provided some new clues for scar formation, and served as a valuable resource for the treatment of central nervous system injury.
Mice ; Animals ; Gliosis/pathology* ; Cicatrix/pathology* ; Spinal Cord Injuries ; Astrocytes/metabolism* ; Spinal Cord/pathology* ; Fibrosis ; Mammals ; Receptors, G-Protein-Coupled

Objective: To investigate the clinicopathological features and possible mechanisms of burned-out testicular germ cell tumors. Methods: The clinical and imaging data, histology and immunophenotypic characteristics of three cases of burned-out testicular germ cell tumors diagnosed at the Ruijin Hospital, Medical College of the Shanghai Jiaotong University, from 2016 to 2020 were retrospectively analyzed. The relevant literature was reviewed. Results: The mean age of the three patients was 32 years. Case 1 had an elevated preoperative alpha-fetoprotein level (810.18 μg/L) and underwent "radical pancreaticoduodenectomy and retroperitoneal lesion resection" for a retroperitoneal mass. Postoperative pathology showed embryonal carcinoma, which needed to exclude gonadal metastasis. Color Doppler ultrasound showed a solid mass of the right testis, with hypoechoic lesion and scattered calcification in some areas. Case 2 was a "right supraclavicular lymph node biopsy specimen." Chest X-ray showed multiple metastases in both lungs. The biopsy showed metastatic embryonic carcinoma and bilateral testicular color Doppler ultrasound revealed abnormal calcifications in the right testicle. Case 3 showed a cystic mass of the right testis with calcification and solid areas. All 3 patients underwent radical right orchiectomy. Grossly, borders of the testicular scar areas were well defined. Cross sectioning of the tumors showed a gray-brown cut surface and single focus or multiple foci of the tumor. The tumor maximum diameter was 0.6-1.5 cm. Microscopically, lymphocytes, plasma cells infiltration, tubular hyalinization, clustered vascular hyperplasia and hemosiderin laden macrophages were found in the scar. Atrophic and sclerotic seminiferous tubules, proliferation of clustered Leydig cells and small or coarse granular calcifications in seminiferous tubules were present around the scar. Seminoma and germ cell neoplasia in situ were seen in case 1, germ cell neoplasia in situ was seen in case 2 and germ cells with atypical hyperplasia were seen in case 3. Immunohistochemistry showed that embryonic carcinoma expressed SALL4, CKpan(AE1/AE3) and CD30, seminoma and germ cell tumor in situ expressed OCT3/4, SALL4 and CD117, and spermatogenic cells with atypical hyperplasia expressed CD99 and SALL4. The Ki-67 positive index was about 20%, while OCT3/4 and CD117 were both negative. Conclusions: Burned-out testicular germ cell tumors are rare. The possibility of gonad testicular metastasis should be considered first for extragonadal germ cell tumor. If fibrous scar is found in testis, it must be determined whether it is a burned-out testicular germ cell tumor. The burned-out mechanisms may be related to the microenvironment of tumor immune-mediated and local ischemic injury.
Male ; Humans ; Adult ; Seminoma/secondary* ; Cicatrix/pathology* ; Hyperplasia ; Retrospective Studies ; China ; Testicular Neoplasms/pathology* ; Neoplasms, Germ Cell and Embryonal/surgery* ; Calcinosis ; Carcinoma ; Tumor Microenvironment

Objective:This study aimed to explore the safety and feasibility of gasless transoral vestibular robotic resection of thyroglossal duct cysts. Methods:The clinical data of patients who underwent gasless transoral vestibular robotic resection of thyroglossal duct cysts at the Department of otolaryngology, Sun Yat-sen Memorial Hospital, Sun yat-sen university from September 2020 to May 2022 were analyzed. The operative time, blood loss, postoperative complications, postoperative pain score, postoperative aesthetic score, and recurrence were prospectively evaluated. Results:All patients completed the operation successfully and no case conversed to an open operation. The operation time was 104.00（95.00, 131.25） minutes, and the surgical blood loss was 15.00（10.00, 16.25） mL. The drainage volume was（59.71±9.20） mL. Postoperative pathology was consistent with thyroglossal duct cysts. There was no local reswelling, subcutaneous hematoma, emphysema, skin flap necrosis, infection and other complications. The postoperative hospital stay was 3.00（2.00, 3.00） days. Six patients had mild sensory abnormalities of the lower lip 3 months after surgery, and all patients were satisfied with the cosmetic outcomes. No recurrence was found during the 5-26 months follow-up. Conclusion:gasless transoral vestibular robotic resection of thyroglossal duct cysts is safe and feasible, with hidden postoperative scars and good cosmetic outcomes. It can provide a new choice for patients with thyroglossal duct cysts.
Humans ; Robotic Surgical Procedures ; Thyroglossal Cyst/pathology* ; Postoperative Complications ; Cicatrix/pathology* ; Pain, Postoperative

Objective: To explore the effects of pulsed dye laser (PDL) and ultra-pulsed fractional carbon dioxide laser (UFCL) combined with multipoint microinjection of triamcinolone acetonide in the treatment of red hypertrophic scar at early stage in burn children. Methods: A retrospective cohort before-after control study in the same patients was conducted. From February 2019 to December 2020, a total of 67 burn children who met the inclusion criteria (32 males and 35 females, aged 1 to 12 years) with red hyperplastic scar at early stage, were treated in Hunan Provincial People's Hospital (1^st Affiliated Hospital of Hunan Normal University). All the children were treated with composite laser technique (PDL and UFCL) combined with triamcinolone acetonide (hereinafter referred to as combined treatment). After 2 months, they received the second combined treatment. Before the first combined treatment and 6 months after the last combined treatment, the scar of children was evaluated with the patient and observer scar assessment scale (POSAS) by physicians and family members. Six months after the last combined treatment, the satisfaction of the patients' family members with the efficacy was recorded and the overall satisfaction rate was calculated. Adverse reactions were recorded throughout the treatment process. Data were statistically analyzed with paired sample t test. Results: Six months after the last combined treatment, the POSAS scores of children on the thickness, blood vessels distribution, color, surface roughness, texture, scope, and overall evaluation of scar evaluated by the physicians, and the POSAS scores of children on the color, degree of pain, degree of itching, hardness, thickness, shape and size, and overall evaluation of scar evaluated by the family members were significantly lower than those before the first combined treatment (with t values of 17.32, 16.73, 15.00, 14.91, 19.62, 28.74, 29.83, 17.43, 20.52, 29.01, 28.82, 24.91, 20.30, and 42.13, respectively, P<0.01). Six months after the last combined treatment, 62 (93%), 3 (4%), and 2 (3%) children's family members were very satisfied, satisfied, and relatively satisfied with the treatment effect, respectively, and the overall satisfaction rate was 97% (65/67). Six months after the last combined treatment, no scar thickening or infection occurred in all the wounds of children. Conclusions: Composite laser technique combined with multipoint microinjection of triamcinolone acetonide in the treatment of red hypertrophic scar at early stage in burn children can improve the appearance and texture of scar, reduce scar pain and pruritus, with high satisfaction of children's family members to the treatment effect and less adverse reactions.
Burns/therapy* ; Child ; Cicatrix, Hypertrophic/pathology* ; Female ; Humans ; Lasers, Gas ; Male ; Microinjections ; Pain ; Pruritus ; Retrospective Studies ; Treatment Outcome ; Triamcinolone Acetonide/therapeutic use*

Hypertrophic scar is a pathological repair result of excessive accumulation of extracellular matrix after skin damage, which affects the appearance and function of patients with varying degrees. The degree of scar formation is directly related to the strength of inflammatory reaction during wound healing, and excessive or prolonged inflammatory response increases the incidence of hypertrophic scars. Interleukin-6 (IL-6) is a pleiotropic cytokine that is involved in regulating the fibrotic network composed of fibroblasts, macrophages, keratinocytes, and vascular endothelial cells, and is closely related to the formation of hypertrophic scars. This article reviews the role of IL-6 and its signaling pathway in hypertrophic scar formation.
Cicatrix, Hypertrophic/pathology* ; Endothelial Cells/metabolism* ; Fibroblasts/metabolism* ; Humans ; Interleukin-6 ; Skin/pathology* ; Wound Healing/physiology*

Complete wound regeneration preserves skin structure and physiological functions, including sensation and perception of stimuli, whereas incomplete wound regeneration results in fibrosis and scarring. Amniotic fluid stem cells (AFSCs) would be a kind of cell population with self-renewing and non-immunogenic ability that have a considerable role in wound generation. They are easy to harvest, culture, and store; moreover, they are non-tumorigenic and not subject to ethical restrictions. They can differentiate into different kinds of cells that replenish the skin, subcutaneous tissues, and accessory organs. Additionally, AFSCs independently produce paracrine effectors and secrete them in exosomes, thereby modulating local immune cell activity. They demonstrate anti-inflammatory and immunomodulatory properties, regulate the physicochemical microenvironment of the wound, and promote full wound regeneration. Thus, AFSCs are potential resources in stem cell therapy, especially in scar-free wound healing. This review describes the biological characteristics and clinical applications of AFSCs in treating wounds and provide new ideas for the treatment of wound healing.
Humans ; Amniotic Fluid ; Wound Healing/physiology* ; Regeneration/physiology* ; Skin/pathology* ; Cicatrix ; Stem Cells

The wound healing time, tension of wound edge, proliferation of fibroblast, and extracellular matrix deposition are the important factors of scar formation, and botulinum toxin type A can regulate the above. Prevention and treatment of scar with botulinum toxin type A is one of the hot topics of clinical research in recent years. This paper briefly reviews researches by scholars at home and abroad on the mechanism, clinical application, complications, and adverse effects of botulinum toxin type A in scar prevention and treatment.
Botulinum Toxins, Type A/therapeutic use* ; Cicatrix/prevention & control* ; Extracellular Matrix/pathology* ; Fibroblasts/drug effects* ; Humans ; Wound Healing/drug effects*

OBJECTIVES: Steroidal anti-inflammatory drugs have certain side effects in the treatment of hypertrophic scar, and the scar recurrence is easy after withdrawal of steroid anti-inflammatory drugs. Finding reliable alternative drugs is an effective means to improve this defect. Aspirin, a traditional non-steroidal anti-inflammatory drug, is safe for topical use and has anti-inflammatory effects similar to those of steroidal anti-inflammatory drugs, which may have similar effects on the treatment of hypertrophic scar. This study aims to investigate the inhibitory effect of aspirin on the proliferation of hypertrophic scar in rabbit ears and the underlying mechanism. METHODS: The rabbit ear hypertrophic scar models were prepared. The rabbits were randomly divided into a normal skin group (group A), a blank control group (group B), a 0.9% NaCl group (group C), a 0.2% aspirin group (group D), a 0.5% aspirin group (group E), a 2% aspirin group (group F), and a triamcinolone acetonide group (group G). Macroscopic observation of hyperplasia was performed 8 weeks after local injection of the scar, followed by collecting the scar tissue samples for HE staining, Masson staining, and immunohistochemistry, respectively to assess the proliferation of fibroblasts and collagen fibers, and calculate the hypertrophic index, microvessel density, and immunohistochemical score. RESULTS: All rabbit ear hypertrophic scar models were successfully constructed. In groups B and C, the hypertrophic scar edge was irregular, with reddish protruding epidermis, significant contracture and hard touch. In group D, E, and F, with the increase of aspirin administration concentration, the scar became thinner and gradually flat, the proliferation of fibrocytes and collagen fibers was weakened, and the hypertrophic index was gradually decreased (P<0.05). Immunohistochemistry showed that the expression of β-catenin was decreased in the group D, E and F in turn, and the immunohistochemical score was gradually decreased (P<0.05). There was no significant difference in hypertrophic index, microvessel density, and immunohistochemical score (all P>0.05). CONCLUSIONS Local injection of aspirin can reduce the generation of hypertrophic scar in a dose-dependent manner within a certain concentration range; aspirin inhibits the growth of hypertrophic scar in rabbit ears by inhibiting Wnt/β-catenin signal pathway; 2% aspirin and 40 mg/mL triamcinolone acetonide have similar curative efficacy on hypertrophic scar.
Animals ; Anti-Inflammatory Agents/therapeutic use* ; Aspirin/therapeutic use* ; Cicatrix, Hypertrophic/pathology* ; Collagen ; Rabbits ; Signal Transduction ; Triamcinolone Acetonide/therapeutic use* ; beta Catenin/metabolism*