TGF-β1

Research into the protective effects of two anti-inflammatory molecules, transforming growth factor-beta1 (TGF 1) and Heligmosomoides polygyrus TGM (HpTGM), following heart attack found that both proteins reduced the inflammatory response within the injured heart and reduced mature scarring. Anti-inflammatory therapy to treat patients following acute myocardial infarction is an exciting prospect that deserves further translational studies, report investigators. Research into the protective effects of two anti-inflammatory molecules, transforming growth factor-beta1 (TGFβ1) and Heligmosomoides polygyrus TGM (HpTGM), following heart attack found that both proteins reduced the inflammatory response within the injured heart and reduced mature scarring. Anti-inflammatory therapy to treat patients following acute myocardial infarction is an exciting prospect that deserves further translational studies, report investigators in The American Journal of Pathology, published by Elsevier. Patients with acute heart attacks (ST elevation myocardial infarction, or STEMI) are very likely to survive if they undergo timely reopening of the occluded coronary artery (coronary reperfusion) in specialized clinical centers. Despite the given survival rates and major improvements in treatment, progression to heart failure still represents a major clinical problem. The patients' longer-term outcomes depend on the extent of the damage to their heart tissue. Lead investigator Helen M. Arthur, PhD, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, explains: "Coronary reperfusion after STEMI is standard therapy to salvage ischemic heart muscle. However, evidence suggests that the subsequent inflammatory response that the body initiates to repair the damaged heart tissue can also cause further loss of viable heart muscle. The more muscle that is lost, the greater the risk of subsequent progression to heart failure. The reason for this study was to investigate the potential protective effects of TGFβ1as a possible intervention to minimize this additional damage to the heart beyond the ischemic damage caused by the heart attack itself." The research team found that levels of an important anti-inflammatory protein TGFβ1 in the blood of STEMI patients 24 hours after reperfusion correlated with a reduction in infarct size after three months. To investigate this further they used an established mouse model of a heart attack to test the protective effects of TGFβ1, a protein known to be released in the body in response to tissue injury. They also studied its mimic HpTGM, a protein produced by a parasitic worm to help evade the immune response and thereby enable the worm to live within the tissue lining the gut. Intravascular delivery of either of these naturally occurring anti-inflammatory proteins reduced the injurious inflammatory response within the heart and importantly, the extent of heart injury as evidenced by reduced mature scar size. The investigators were surprised to find almost identical beneficial effects of TGFβ1 and HpTGM treatment. Although TGFβ1 and HpTGM are evolutionarily unrelated, both these molecules interact with cells in a similar manner by activating the same signalling pathway. The dose of anti-inflammatory therapy was given at the time of reperfusion, which corresponds to a clinically useful time for a therapeutic intervention in humans. Investigators could attribute the beneficial outcomes to the protective effect of these molecules on endothelial cells -- the cells lining the blood vessels that help to regulate the exit of proinflammatory white blood cells from the circulation and enter the injured tissue. TGFβ1 has well-established anti-inflammatory properties, whereas HpTGM is a parasitomimetic with great clinical potential. Recent work in the Maizels laboratory at the University of Glasgow has also shown that delivery of HpTGM has a major anti-inflammatory effect in mouse models of colitis or airway inflammation, taking advantage of the product evolved by a parasite to quell the immune response to its presence. Dr. Arthur concluded: "The current study shows that exogenous delivery of HpTGM at the time of coronary artery reperfusion dampens the proinflammatory response of coronary endothelial cells and reduces cardiac injury, leading to increased myocardial salvage and reduced scar size with the corollary of improved prospects for long-term cardiac function. The use of HpTGM as an anti-inflammatory therapy in treating heart attack patients is clearly an exciting prospect that requires further translational studies."

Research exploring CK0804 (CXCR4-enriched, allogeneic, cord blood-derived T-regulatory cells) for treatment of myelofibrosis patients. HOUSTON and NEW YORK, April 1, 2024 /PRNewswire/ -- Cellenkos®, a clinical stage biotech cell therapy company focused on treating autoimmune diseases and inflammatory disorders, today announced that it has entered into a sponsored research agreement with the Icahn School of Medicine at Mount Sinai, New York, to explore the application of CK0804, CXCR4 enriched, allogeneic, cord blood T regulatory (Treg) cells, for treatment of myelofibrosis. This research will be conducted under the guidance of Ronald Hoffman, MD, Albert A. and Vera G. List Professor of Medicine and Director of the Myeloproliferative Disorders Research Program at The Tisch Cancer Institute- Mount Sinai. "We are very excited by our collaboration with Mount Sinai and eagerly anticipate gaining a deeper understanding of mechanisms of CK0804 Tregs work in myelofibrosis, especially to decrease inflammation," said Tara Sadeghi, Chief Operating Officer, Cellenkos Inc. "CK0804 is already in phase 1 clinical trial to examine its safety and efficacy in patients with myelofibrosis who have suboptimal response to the JAK2 inhibitor, ruxolitinib. We are particularly intrigued by the possibility of using CK0804 in treatment naïve myelofibrosis patients as well as in combination with other approved therapies including ruxolitinib, momelotinib, pacritinib and fedratinib." "We are eager to find out if this novel cell therapy product has the potential to transform the care of myelofibrosis patients," said Dr. Ronald Hoffman, principal investigator, "We will investigate the role of Treg cells in the pathogenesis of the myeloproliferative neoplasms and examine the effectiveness of CK0804, especially in patients with low blood counts." CK0804 is a novel allogeneic, CXCR4 enriched, Treg cell therapy product that utilizes Cellenkos' proprietary CRANE® technology to generate disease specific products. CK0804 engage with CXCL12 ligand and preferentially home to the inflamed bone marrow. When compared to control, CK0804 significantly decrease TGFβ1 and TGFβ2, in vivo. The ongoing, multicenter, first-in-human, Phase 1b trial, shows safety of multiple doses of CK0804 in myelofibrosis patients in the ambulatory setting as well as improvement in their blood transfusion requirements, spleen volume reduction and symptom burden. The ability to administer CK0804 cells in ambulatory setting without requiring lymphodepletion or immune suppression, positions this potentially lifesaving treatment to be made available to patients in the community setting. The trial is open for accrual at Albert Einstein Hospital, Bronx, NY, MD Anderson Cancer Center, Houston, TX and University of California Davis, Sacramento, CA. ClinicalTrials.gov ID NCT05423691. Dr. Ronald Hoffman serves as a paid consultant for Cellenkos. About Cellenkos®, Inc. Cellenkos is a clinical-stage biotechnology company located in Houston, Texas, USA, dedicated to the development and commercialization of the allogeneic, "off-the-shelf" cell-based products for the treatment of rare inflammatory diseases and autoimmune disorders. Cellenkos' T regulatory cells (Tregs) are derived from umbilical cord blood and as such are naïve, bonafide suppressor cells that do not require HLA or ABO matching and resolve inflammation through multiple direct and indirect mechanisms. Cellenkos' proprietary CRANE® technology platform tailors Tregs to home to target tissue. Cellenkos' current clinical portfolio includes CK0801 (bone marrow failure); CK0802 (COVID associated acute respiratory distress syndrome); CK0803 (Amyotrophic Lateral Sclerosis) and CK0804 (myelofibrosis). For more information, please visit . Contact: Stacy Minor [email protected]. SOURCE Cellenkos, Inc.

关注并星标CPHI制药在线       皮肤是机体最大的器官，具有屏障、吸收、感觉、体温调节、代谢、免疫等多种生理功能。大面积皮肤烧伤、皮肤良恶性肿瘤、皮肤色素性疾病等引起的皮肤损伤严重影响患者健康。其中，皮肤烧伤不仅破坏皮肤的屏障功能，还改变皮肤的痛觉、温觉、触觉等。研制含皮肤附属器的功能性组织工程全层皮肤是解决大面积皮损的有效途径，具有重要的研究价值。近年来，随着组织工程学的飞速发展，发现间充质干细胞（MSCs）是构建全层皮肤的理想种子细胞，在治疗皮肤创伤方面展现了良好的应用前景。       1、皮肤愈合的过程和机制       皮肤损伤修复需要经过皮肤细胞严密的编排、整合及分化、迁移、增殖和凋亡过程，才能实现皮肤多层结构的再生。皮肤损伤的修复可以概括为以下 4 个时期：①血液凝固期：损伤初期血小板和凝血因子被激活，启动内、外源性凝血途径实现凝血；②炎症反应期：中性粒细胞、单核细胞和巨噬细胞增多，通过吞噬异物和调节炎症因子的释放调控炎症反应；③细胞增殖期：包括通过成纤维细胞增殖介导肉芽组织形成、通过角质细胞介导再上皮化和通过内皮细胞增殖介导血管生成等过程；④组织重塑期：随着细胞外基质（extracellular matrix，ECM）的分泌和肉芽组织的增生，成纤维细胞分裂合成大量胶原纤维，新生血管增多。后期在基质金属蛋白酶（matrix metalloproteinase，MMPs）作用下，降解 ECM，胶原蛋白发生新陈代谢，最终导致瘢痕的形成。       2、MSCs促进创伤愈合、抑制瘢痕形成机制       ①免疫调节作用。在组织损伤发生后，伤口处炎症环境会直接刺激MSCs发挥其特有的免疫调节作用，包括增强环氧合酶2的活性，上调前列腺素E2（prostaglandin E2，PGE2）等。在PGE2的影响作用下，T 细胞和巨噬细胞开始重新编程并开始表达高浓度的IL-10，而研究发现IL-10 对无瘢痕修复必不可少，其过量表达能明显抑制瘢痕的形成。MSCs 抑制中性粒细胞侵入到伤口处，以防止嗜中性粒细胞释放的活性氧（reactive oxygen species，ROS），进一步引起机体组织氧化损伤；IL-10 也可通过直接下调巨噬细胞和T细胞中TGF-β1 的表达、重新编码成纤维细胞、上调基质金属蛋白酶（matrix metalloproteinases，MMPs）的表达、下调胶原的表达促进细胞外基质的重塑以达到抗纤维化的目的。此外，IL-10 还能通过减少促炎因子IL-6 及IL-8 的表达来达到抑制胶原过度沉积。       ②分泌一氧化氮中和活性氧。MSCs 可以促进氧化氮合酶的产生，通过改变 ROS/RNS 的平衡来有效地抑制纤维化组织的形成。在创伤开始的炎症期，中性粒细胞分泌胶原过度沉积的增强剂如超氧化物、过氧化氢以及烷基过氧化物等大量的ROS。ROS的主要作用是对膜磷脂产生氧化作用以及通过对TGF-β1的诱导而促进纤维化的发生。MSCs可促使ROS 转变为活性氮分子（reactive nitrogen species，RNS），如过氧硝酸盐等，减缓对DNA和膜磷脂的损伤，从而抑制纤维化的发生。       ③分泌具有抗纤维化生长因子。研究表明，MSCs可分泌各种细胞因子和生长因子，一些因子具有抗纤维化的作用，如肝细胞 生长因子（hepatocyte growth factor，HGF）、IL-10 以及肾上腺髓质素等。HGF 在减轻纤维化以及抑制皮肤瘢痕形成的机制主要包括：一是对成纤维细胞功能的调节，在HGF的存在情况下，HGF 受体通过绑定中和TGF-β/Smad 信号通路的下游信号级联反应，抑制SMAD3 蛋白的促炎基因的转录因子作用，成纤维细胞下调 TGF-β1、Ⅰ型和Ⅲ型胶原的表达，还可以刺激成纤维细胞 MMP 家族 MMP-1、MMP-3及MMP-13 表达的上调，促使ECM发生逆转。二是HGF通过促进角化细胞的迁移增殖，并上调血管内皮 生长因子A（vascular endothelial growth factor-A，VEGF-A）的表达，促使创伤处生成高质量的并且血运丰富的肉芽组织，促进伤口的上皮化的形成。三是HGF可抑制各种来源的肌成纤维细胞的分化，HGF可以抑制创伤处的成纤维细胞向肌成纤维细胞分化。       ④调节皮肤成纤维细胞的数量及功能。MSCs可作用于损伤处的成纤维细胞来调控细胞外基质的产生，使损伤皮肤的修复更接近于正常皮肤。在创伤修复过程中，皮肤恢复其完整性必须要有成纤维细胞的参与，但是这些成纤维细胞会产生过多的 ECM，从而导致瘢痕的产生。在创伤处的MSCs 通过分泌的生物活性分子包括HGF、PGE2 等可以抑制血管内皮细胞 EMT，也可以抑制肌成纤维细胞的分化。另外，在修复过程中，MSCs 还可通过旁分泌分泌生物活性因子促进成纤维细胞的功能。       ⑤促进组织的血管再生及血管稳定。创伤修复过程中的炎症阶段、上皮形成期、成熟期等都必须依靠新生的毛细血管和结缔组织即肉芽组织的增殖和修补来完成，在增殖阶段，血管再生可为肉芽组织形成提供营养。在血管系统重塑的过程中，除巨噬细胞及成纤维细胞外，MSCs也会分泌促进血管化的细胞因子包括成纤维细胞生长因子、VEGF-A等，促进微血管内皮细胞的增殖、迁移以及分化。另外，MSCs 还可通过旁分泌（如分泌肾上腺髓质素等）来促进血管的稳定保护脉管系统。       ⑥可分化为各种皮肤细胞。MSCs都具有典型的成骨、成脂及成软骨的分化能力，这也类似于在创伤部位各种来源的成纤维细胞向肌成纤维细胞转化一样，是一个表型的转化。研究表明，MSCs 可分化为各种皮肤细胞，包括表皮细胞、角化细胞、小血管内皮细胞等，直接参与到表皮和真皮结构再生过程，达到促进皮肤创伤愈合的目的。       3、提高MSCs修复皮肤损伤效率的有效途径       目前应用MSCs促进皮肤损伤修复的方法主要是局部注射和静脉注射。局部注射一般是将MSCs注射至创面的周围，但由于注射的面积和深度难以控制，并不能让MSCs直接、均匀地分布在创面上。静脉注射则不能保证所有MSCs都参与皮肤修复，且MSCs分泌的外泌体在体内很快会被清除，难以维持较高浓度状态，需多次给药。此外，注射的方法还会对皮肤造成二次伤害，给治疗带来一定的困难。这些问题使得间充质干细胞的最终治疗潜力受到限制，达不到其应有的修复效果。因此，人们也对如何提高 MSCs 的修复效率做了许多探索，取得了较为丰富的研究进展。       ①生物支架。生物支架具有良好的生物相容性和生物降解性，可将干细胞输送到伤口处。常见的用于促进皮肤损伤修复药物递送的生物支架材料分为天然支架和合成支架。天然支架的材料成分包括透明质酸、壳聚糖、胶原蛋白、海藻酸盐等，合成支架材料成分包括聚乙二醇、聚乳酸-羟基乙酸等。目前，对于皮肤损伤应用最多的支架形式为水凝胶支架，它可以使外泌体在皮肤局部应用后浓度更加稳定，以延迟外泌体的释放并增强其伤口愈合能力。水凝胶是一种稳定的亲水性网络结构，通过物理、化学和生物酶法交联而成，具有良好的生物相容性、可降解性和保水性等，已被证实是最友好、经济并容易获得的材料，在临床医学中显现出极大的应用潜力。水凝胶负载间充质干细胞来源的外泌体（MSC-EXOs）既可解决静脉注射法造成的外泌体在体内被快速清除的问题，又可以将含有外泌体的水凝胶直接放置于目标部位或其附近，能够保证外泌体的作用剂量更加集中，同时发挥外泌体和水凝胶促进伤口修复的作用。       ②预处理。通过某些预处理可以改善 MSCs 的生化和生物物理特性，从而增强其修复功能。研究发现内皮细胞培养基预处理的脂肪MSCs 在体外和糖尿病小鼠创伤模型中均显示出血管生成能力、增殖能力和向内皮分化能力的增强。MSCs 还可以经过一些化学物质的预处理提高修复皮肤损伤的能力。如使用卵磷脂乳化的鸸鹋油和丁基羟基甲苯处理脂肪 MSCs，显著提高了其再生潜力。此外，也有人尝试用生物玻璃材料激活尿液来源的MSCs，通过刺激 MSCs 与受体细胞之间以及成纤维细胞与内皮细胞之间的旁分泌效应来提高小鼠皮肤的愈合能力。       ③低氧环境。研究表明，缺氧可以提高 MSCs 的皮肤创伤愈合能力。在小鼠伤口愈合模型中植入人羊膜MSCs，发现与正常条件下培养的 MSCs 相比，缺氧条件下培养的 MSCs 具有更高的生存能力和增殖能力，并增加了血管内皮 生长因子的表达。这些MSCs 还提高了人真皮成纤维细胞的活力和迁移率，增加了细胞外基质的表达，加速了伤口愈合。此外有研究人员发现低氧环境下，小鼠的骨髓 MSCs在体外分泌了更多的碱性纤维母细胞生长因子、血管内皮 生长因子 A 和白细胞介素-6。在体内实验也发现移植的骨髓 MSCs 在低氧环境下能使皮肤伤口收缩明显加快，体内细胞增殖、新生血管形成速度明显提升。       ④基因重组。对 MSCs 进行基因重组，将 MSCs 既用作种子细胞又用作将目的基因传递到伤口部位的载体，也是一种很有前景的治疗皮肤损伤的手段。有研究针对 MSCs 进行基因改造，通过改变其活性来增强其修复皮肤损伤的能力。例如，过表达转化生长因子-β3的骨髓 MSCs 不仅改善了家兔耳部伤口愈合过程，而且减少了瘢痕组织的形成。研究人员使用重组慢病毒载体修饰人羊膜 MSCs 过表达白细胞介素-10，发现其在加速小鼠伤口愈合、促进血管生成、调节炎症、调节 ECM 重构、促进创面愈合和提高愈合质量方面等方面明显强于未修饰的 MSCs。       ⑤细胞膜片技术。细胞膜片是一种无支架的细胞密集组织。由于细胞密度是提高细胞移植治疗效果的重要因素之一，与单细胞片相比，移植构建的分层细胞片可以更好地促进组织功能的恢复和组织再生。研究报道，以血卟啉包合聚酮膜为材料，将骨髓MSCs 接种到膜上后敷在小鼠伤口上，这种三层细胞片移植和堆叠的方法促进了小鼠创面血管生成和皮肤再生，增强了受损皮肤组织的修复。       尽管 MSCs 的应用无法复制胚胎式的创伤修复，而使成人的创伤修复达到无瘢痕的完美修复，但它仍然可存在巨大的治疗潜能。在皮肤创面修复愈合过程中，通过抑制皮肤瘢痕的形成达到提高创面愈合质量已成为当前皮肤再生修复研究的新目标，此时，MSCs 巨大的治疗潜能则成为抑制皮肤瘢痕形成的新策略，为创面修复提供一种新的视角和治疗手段。       参考资料       [1]张立,王强.间充质干细胞在皮肤损伤修复中的作用研究[J].中国临床医学,2015,22(04):571-574.   [2]武艳,张哲,杨岚等.间充质干细胞在创伤愈合过程中抑制瘢痕形成的作用机制[J].中国医药导报,2016,13(09):47-50.       [3]程延思危,宋关斌.间充质干细胞与皮肤的损伤修复[J].生物医学工程学杂志,2021,38(02):387-392.       作者简介：小泥沙，食品科技工作者，食品科学硕士，现就职于国内某大型药物研发公司，从事营养食品的开发与研究。【智药研习社近期课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~