miR-21在皮肤相关疾病及创伤愈合中的作用

microRNA-21(miR-21)是一种内源性非编码RNA,在细胞增殖、分化过程中发挥了重要的调控作用。近年来，miR-21作为广泛研究的miRNA,其在皮肤相关疾病及创伤愈合中的作用备受关注。研究表明，miR-21作为一个“广泛因子”,通过抑制不同靶基因(PTEN、TIMP、PDCD4等)的转录翻译过程，影响不同细胞(角质形成细胞、T细胞、纤维细胞等)的增殖、凋亡、迁移和侵袭。同时，还能通过不同信号通路，促进炎症的发生，在皮肤肿瘤、皮肤免疫性疾病、皮肤炎症性疾病、皮肤创伤及瘢痕组织形成中发挥重要作用。本文回顾了miR-21在不同的皮肤疾病(黑色素瘤、皮肤鳞状细胞癌、T细胞淋巴瘤、银屑病、硬皮病等)和创伤愈合中的参与机制，旨在深化对miR-21分子在皮肤相关疾病和创伤愈合中的认识，表明miR-21除了有作为皮肤性疾病诊断的生物标志物潜力和评价药物疗效的能力外，更有望成为一种新型的治疗手段，为临床治疗难题提供新方向。     

MicroRNA 在皮肤创伤愈合中的作用

皮肤创伤愈合过程是一个复杂而连续的过程,这一过程需要多种细胞、多种因子的参与,涉及细胞增殖、细胞分化、细胞运动、细胞黏附等多个细胞生物学过程。 MicroRNA（ miRNA）是一类高度保守的非编码RNA,它通过靶向结合信使RNA（ mRNA）并使其降解或抑制其翻译,实现转录后基因表达调控。 miRNA作为基因表达的重要调控分子,几乎参与了机体所有的生理和病理过程。除了在皮肤发育中发挥重要的作用,还参与多种皮肤病、皮肤癌和皮肤创伤愈合过程的调节。主要总结了miRNA调控皮肤创伤愈合的研究进展。     

外泌体在皮肤修复与再生中作用的研究进展

外泌体是直径在30-100 nm左右的囊泡结构。作为一种活细胞分泌的亚细胞成分,外泌体广泛参与细胞之间的交流,并可以作为干细胞的旁分泌因子来发挥生物学效应。研究发现外泌体可以参与皮肤组织修复与再生的各个过程,通过促进皮肤细胞的增殖迁移,促进血管新生,调节免疫反应来促进创伤愈合与皮肤组织再生,为进一步实现无细胞治疗提供了新的实现途径。对于某些慢性创面,例如糖尿病性皮肤溃疡等也有较好的治疗效果。本文就外泌体在皮肤修复与再生中作用的研究进展做一综述。     

RBM10通过影响miR-21稳定性参与调控人乳腺癌细胞增殖及转移活性

目的:分析miR-21和RNA结合基序(RBM)在人乳腺癌组织及相应肿瘤细胞中的表达相关性和功能联系。方法:通过Oncomine或starBase数据库分析miR-21和RBM10表达数据,揭示其在人乳腺癌和对照组织中的表达差异;采用人乳腺癌细胞MCF-7、MDA-MB-231和永生化的人乳腺正常上皮细胞MCF-10A进一步分析miR-21和RBM10在乳腺癌细胞和正常乳腺细胞中的表达差异;采用CCK-8法检测敲低RBM10对MCF-7细胞增殖的影响;采用Transwell实验检测敲低RBM10对MCF-7细胞侵袭与迁移能力的调控差异;用放线菌素D处理MCF-7细胞,检测不同时间点miR-21的相对含量反映其稳定性。结果:生物信息学分析结果显示miR-21和RBM10在乳腺癌组织中显著高表达;与组织表达结果类似,在乳腺癌细胞中miR-21和RBM10的表达量显著高于正常乳腺细胞;miR-21与RBM10的表达呈正相关;敲低RBM10抑制MCF-7细胞的增殖、迁移与侵袭,而同时过表达miR-21会减弱这种抑制效应;敲低RBM10能够显著降低miR-21的稳定性。结论:RBM10通过影响miR-21的稳定性参与调控人乳腺癌细胞功能活性。RBM10在肿瘤中的作用仍有待进一步研究,不能简单地概括为一种抑癌因子或致癌因子。     

血管发育相关microRNAs的研究进展

脊椎动物血管系统的发育是一个极其重要且复杂的过程。MicroRNAs在转录及转录后水平对基因表达起调控作用,参与了诸多重要的生理、病理过程。MicroRNAs主要在血管平滑肌细胞和血管内皮细胞的发育调控中发挥着重要作用。本文归纳了近年来有关microRNAs在血管发育中的研究进展,着重阐述了miR-126、miR-17/92家族等在血管内皮细胞中的调控作用机制,以及miR-143/145家族、miR-21等在血管平滑肌细胞中的调控作用机制。本文还对microRNAs在血管发育中作用的研究前景作了展望。     

miR-20b-5p在肿瘤及其他疾病中的生物学功能

miRNAs是一类非编码的小RNA分子,在多种疾病的发病和治疗中发挥重要作用,可调控细胞增殖、细胞周期、凋亡和迁移等过程中关键基因的表达。miR-20b-5p属于miR-17家族,在多种肿瘤中和非肿瘤性疾病中存在异常表达。在肿瘤中,miR-20b-5p扮演着癌基因或抑癌基因的角色,可通过调控相应靶分子的表达影响肿瘤细胞的增殖、凋亡、侵袭与迁移等生物学行为,进而促进或抑制肿瘤的发生发展。该文对miR-20b-5p在肿瘤和非肿瘤性疾病中的生物学功能和机制进行简要综述。相信随着对miR-20b-5p的功能和机制的深入阐明,miR-20b-5p有望作为多种疾病的诊治靶点。     

miR-106a在肿瘤中的研究进展

miR-106a是一种致瘤性的miRNA,在多种肿瘤中表达发生变化并与肿瘤耐药性密切相关。miR-106a通过调控多种靶基因,在细胞增殖、细胞凋亡、细胞迁移和自噬等过程中发挥重要作用。结合临床诊断和预后检测结果,miR-106a很可能成为肿瘤标记物。本文对miR-106a在不同肿瘤中的研究进展进行综述。     

皮肤创伤愈合过程中短暂扩增细胞增生及皮肤干细胞迁移

目的研究皮肤疤痕组织形成过程中皮肤干细胞分布、增殖分化迁移特征,初步探讨这些特征与皮肤创伤修复的关系。方法利用眼科显微外科剪对2日龄昆明小鼠背部皮肤进行人工统一造创,定期获取皮肤创面样品,常规病理染色观察创面愈合形态;应用免疫荧光染色法,以细胞转录因子Sox2和角蛋白14抗体分别检测皮肤干细胞的分布及干细胞增殖分化时所形成的短暂扩增细胞,并结合细胞增殖EdU荧光染色初步分析皮肤干细胞的迁移方向。结果创面愈合过程中表皮层中表达Sox2的阳性细胞逐渐连贯,并且发现真皮乳头层中Sox2和角蛋白14同时大量表达,可见致密细胞网和向下凸起的新生毛囊样结构形成。同时,创面愈合初期细胞迁移主要由创面底部开始,向上迁移并填充创面。结论创面愈合过程中,创面底部皮肤干细胞首先开始大量分裂增殖,并向创面迁移,创面上部皮肤干细胞分裂增殖迟于创面底部;迁移的皮肤干细胞以不对称分裂的形式增殖形成大量短暂扩增细胞,并在增厚的疤痕乳头层部位形成毛囊样结构填充皮肤疤痕。     

调节表皮干细胞增殖和分化的信号通路

表皮干细胞能够维持正常表皮的新陈代谢、毛囊周期循环以及参与创伤情况下创面的修复,皮肤肿瘤的发生也与其密切相关。表皮干细胞的增殖和分化受到严格的调控,了解表皮干细胞增殖与分化的调控机制将有助于治疗脱发、创伤以及皮肤肿瘤等疾病。文章着重概述了Wnt和Bmp信号对于控制干细胞命运的重要作用。     

骨髓间充质干细胞促进皮肤创伤愈合的作用机制及临床应用

皮肤是人体面积最大的器官,不同来源的损伤可使皮肤正常结构遭到破坏,皮肤创面修复过程失衡,从而导致皮肤愈合缓慢或畸形愈合,损害皮肤正常功能。骨髓间充质干细胞因其易获取、体外培养技术简单、低免疫原性、旁分泌、高度自我复制能力及多向分化潜能等特点而使其具有独特的优越性。已有研究表明骨髓间充质干细胞(BMSC)可通过多种复杂机制实现其促进皮肤创面愈合的作用,其趋化性可使BMSC向损伤部位迁移,并在局部分化为多种皮肤细胞、皮肤附属器细胞以及血管内皮细胞,促进皮肤的再生,通过抑制免疫细胞的生物学活性来发挥免疫调节作用。此外,BMSC可以分泌多种重要的生物活性因子,起到抗炎、促进新血管形成、抗纤维化及瘢痕形成、加快伤口愈合等作用。目前,BMSC已运用于多种类型皮肤损伤的临床治疗以及组织工程和再生医学中,且已取得了一定成果。本文主要就骨髓间充质干细胞的生物学特性、促进皮肤创伤愈合的作用机制及其临床应用进行了综述。     

miR-21 promotes keratinocyte migration and re-epithelialization during wound healing

MicroRNAs involved in keratinocyte migration and wound healing are largely unknown. Here, we revealed the indispensable role of miR-21 in keratinocyte migration and in re-epithelialization during wound healing in mice. In HaCaT cell, miR-21 could be upregulated by TGF-β1. Similar to the effect of TGF-β1, miR-21 overexpression promoted keratinocyte migration. Conversely, miR-21 knockdown attenuated TGF-β1-induced keratinocyte migration, suggesting that miR-21 was essential for TGF-β-driven keratinocyte migration. Furthermore, we found that miR-21 was upregulated during wound healing, coincident with the temporal expression pattern of TGF-β1. Consistently, knockdown of endogenous miR-21 using a specific antagomir dramatically delayed re-epithelialization possibly due to the reduced keratinocyte migration. TIMP3 and TIAM1, direct targets of miR-21, were verified to be regulated by miR-21 in vitro and in vivo, indicating that these two molecules might contribute to miR-21-induced keratinocyte migration. Taken together, our results demonstrate that miR-21 promotes keratinocyte migration and boosts re-epithelialization during skin wound healing.     

miR-96-5p regulates wound healing by targeting BNIP3/FAK pathway

Cutaneous wound healing is a highly orchestrated basic biological process and one of the key processes in restoring skin integrity. The role of microRNAs (miRNAs) during this process has raised numerous attention and is poorly explored. The aim of this study is to investigate the potential function of BCL2 interacting protein (BNIP3) and its target miRNA, miR-96-5p, in cutaneous wound healing. The results demonstrated that BNIP3 was significantly increased and miR-96-5p was obviously decreased during wound healing. Overexpression of BNIP3 significantly increased, while inhibition of BNIP3 decreased cell proliferation and migration of human primary keratinocytes. miR-96-5p was predicted to be a target miRNA for BNIP3 and luciferase reporter assay confirmed that miR-96-5p directly targeted the 3′-untranslated region of BNIP3. Moreover, miR-96-5p overexpression significantly decreased, while miR-96-5p inhibition dramatically increased BNIP3 protein expression and focal adhesion kinase (FAK) pathway activation. Furthermore, miR-96-5p inhibited cell proliferation and migration of human primary keratinocytes. Overall, our findings suggest that miR-96-5p might be critical in the regulation of wound healing by mediating BNIP3 and FAK pathway.     

miR-155 promotes cutaneous wound healing through enhanced keratinocytes migration by MMP-2

Inflammation, re-epithelization and tissue remodeling are three essential steps during wound healing. The re-epithelization process plays the most important role which mainly involves keratinocyte proliferation and migration. miR-155 has been reported to participate in cell migration and transformation, however, its function in skin wound healing is largely unknown. Here we hypothesize that overexpression of miR-155 at wound edges could accelerate wound healing mediated by enhanced keratinocyte migration. To test this hypothesis, direct local injection of miR-155 expression plasmid to wound edges was conducted to overexpress miR-155 in vivo. Results shown that miR-155 significantly promoted wound healing and re-epithelization compared to control, while did not affect wound contraction. Also, miR-155 overexpression accelerated primarily cultured keratinocyte migration in vitro, but had no effect on cell proliferation. Importantly, western blot analysis shown that MMP-2 was significantly upregulated whiles its inhibitor TIMP-1 downregulated after miR-155 treatment. Moreover, the use of ARP-101, an MMP-2 inhibitor, effectively attenuated the accelerative effects on cell migration induced by miR-155. Taken together, our results suggest that miR-155 has the promote effect on wound healing that is probably mediated by accelerating keratinocyte migration via upregulated MMP-2 level. This study provides a rationale for the therapeutic effect of miR-155 on wound healing.     

Epithelial–mesenchymal transition in the formation of hypertrophic scars and keloids

Abnormal wound healing is likely to induce the formation of hypertrophic scars and keloids, which leads to dysfunction, deformity, and mental problem in the patients. Despite the advances in prevention and management of hypertrophic scar and keloids, the mechanism underlying scar and keloid formation has not been fully elucidated. Recent insights into the role of the epithelial–mesenchymal transition (EMT) in development, wound healing, stem cell regulation, fibrosis, and tumorigenesis have increased our understanding of the pathophysiology of hypertrophic scarring and keloids and suggested new therapeutic targets. This review summarizes recent progress in the elucidation of the role of EMT in physiologic wound healing and pathologic scar formation. This knowledge will facilitate an understanding of EMT roles in scar formation and shed new light on the modulation and potential treatment of hypertrophic scars and keloids.     

Elastin signaling in wound repair

Skin is an important organ to the human body as it functions as an interface between the body and environment. Cutaneous injury elicits a complex wound healing process, which is an orchestration of cells, matrix components, and signaling factors that re‐establishes the barrier function of skin. In adults, an unavoidable consequence of wound healing is scar formation. However, in early fetal development, wound healing is scarless. This phenomenon is characterized by an attenuated inflammatory response, differential expression of signaling factors, and regeneration of normal skin architecture. Elastin endows a range of mechanical and cell interactive properties to skin. In adult wound healing, elastin is severely lacking and only a disorganized elastic fiber network is present after scar formation. The inherent properties of elastin make it a desirable inclusion to adult wound healing. Elastin imparts recoil and resistance and induces a range of cell activities, including cell migration and proliferation, matrix synthesis, and protease production. The effects of elastin align with the hallmarks of fetal scarless wound healing. Elastin synthesis is substantial in late stage in utero and drops to a trickle in adults. The physical and cell signaling advantages of elastin in a wound healing context creates a parallel with the innate features of fetal skin that can allow for scarless healing. Birth Defects Research (Part C) 96:248–257, 2012. © 2012 Wiley Periodicals, Inc.     

Notch与相关调控信号的相互作用在伤口愈合中的调控

皮肤是哺乳动物最重要的组织之一.当皮肤受损时,受损组织通过系列伤口愈合反应的生理和心理作用被修复,实现组织再生.再生反应主要发生在胚胎发育早期,伤口自愈能力随着机体的成熟而减弱;并且哺乳动物的组织重塑过程较为复杂,在不正确的信号引导下,可能引起并发症而导致创面愈合异常.研究表明,伤口微环境的稳态和信号分子的辅助作用是愈...     

Cytoglobin inhibits migration through PI3K/AKT/mTOR pathway in fibroblast cells

Cell proliferation and migration are crucial in many physiological processes including development, cancer, tissue repair, and wound healing. Cell migration is regulated by several signaling molecules. Identification of genes related to cell migration is required to understand molecular mechanism of non-healing chronic wounds which is a major concern in clinics. In the current study, the role of cytoglobin (CYGB) gene in f?broblast cell migration and proliferation was described. L929 mouse fibroblast cells were transduced with lentiviral particles for CYGB and GFP, and analyzed for cell proliferation and migration ability. Fibroblast cells overexpressing CYGB displayed decreased cell proliferation, colony formation capacity, and cell migration. Phosphorylation levels of mTOR and two downstream effectors S6 and 4E-BP1 which take part in PI3K/AKT/mTOR signaling declined in CYGB-overexpressing cells. Microarray analysis indicated that CYGB overexpression leads to downregulation of cell proliferation, migration, and tumor growth associated genes in L929 cell line. This study demonstrated the role of CYGB in fibroblast cell motility and proliferation. CYGB could be a promising candidate for further studies as a potential target for diseases related to cell migration such as cancer and chronic wound treatment.     

Re‐epithelialization of large wound in paedomorphic and metamorphic axolotls

Axolotls (Ambystoma mexicanum ) may heal their skin wounds scar‐free in both paedomorphs and metamorphs. In previous studies on small punch skin wounds, rapid re‐epithelialisation was noted in these two axolotl morphs. However, large wound size in mammals may affect wound healing. In this study, large circumferential full thickness excision wounds on the hind limbs were created on juvenile paedomorphic and metamorphic axolotls. The results showed re‐epithelialisation was more quickly initiated in paedomorphs than in metamorphs after wounding. The migrating rate of epidermis on the wound bed was faster in paedomorphs than in metamorphs and thus completion of re‐epithelialisation was faster in paedomorphs than in metamorphs. Within these re‐epithelialisation periods, neither basement membrane nor dermis was reformed. Epidermal cell proliferation was detected by EdU‐labelling technique. In the normal unwounded skin, epidermal proliferation rate was higher in paedomorphs than in metamorphs. After wounding, the epidermal proliferation rate was significantly lower in the migrating front on the wound bed than in the normal skin in paedomorphs. The EdU‐labelling rate between normal skin and migration front was not different in metamorphs. Lacking of more proliferating epidermal cells on the wound bed indicated that the new epidermis here derived rather from migrating epidermal cells than from cell proliferation in situ. In conclusion, re‐epithelialisation in the large wound might be fully completed in both morphs despite it was initiated earlier and with faster rate in paedomorphs than in metamorphs. The new epidermis on the wound bed derived mainly from cell migration than by cell proliferation in the re‐epithelialisation period. J. Morphol. 278:228–235, 2017. © 2016 Wiley Periodicals,Inc.     

Growth potential of Rana tigerina skin lipids in cell cultures

Summary This study involves the investigation of the lipid composition of the skin of Rana tigerina which has a significant healing capacity. The results indicated that the lipid extract enhanced keratinocyte and fibroblast cell proliferation progressively and were found to be much more efficient in comparison to agents known to cause cell proliferation and to be anti-inflammatory such as hydrocortisone. Cell proliferation was dose dependent and suppression occurred only at very high doses. [³H]thymidine incorporation studies produced the same results. Because proliferation, migration, and differentiation of the basal cells is essential for initiation and progression of wound healing, any agent enhancing their proliferation would hasten the healing process. This paper therefore aims at elucidating the effect of composition of the total lipid extract confirming the efficacy of frog skin in wound healing and thereby providing an understanding of the natural mechanism of healing.     

LncRNA COL1A2-AS1 inhibits the scar fibroblasts proliferation via regulating miR-21/Smad7 pathway

lncRNA COL1A2-AS1 (COL1A2 antisense RNA 1), a lncRNA overexpressed in hypertrophic scar, has been demonstrated to be involved in the hypertrophic scar formation. However, the mechanisms of lncRNA COL1A2-AS1 inhibiting the scar fibroblasts proliferation remains not well understood. In this study, we demonstrated that lncRNA COL1A2-AS1 was upregulated in hypertrophic scar tissue and fibroblasts, and suppressed fibroblasts proliferation by promoting Smad7 expression. Furthermore, we found that miR-21 was involved in lncRNA COL1A2-AS1-induced expression of Smad7, by which COL1A2-AS1 acted as endogenous sponge to adsorb miR-21 and in turn regulated Smad7 and a cascade of molecular to play a protective role in hypertrophic scar. In addition, overexpression of miR-21 attenuated COL1A2-AS1-mediated proliferation suppression of hypertrophic scar fibroblasts. In conclusion, our study demonstrated that COL1A2-AS1/miR-21/Smad pathway plays an important role in inhibiting hypertrophic scar formation, and suggested this novel pathway may be a new target for hypertrophic scar treatment.