间质干细胞和急性肺损伤专业知识讲座.pptx

Mesenchymal Stem Cells and Acute Lung Injury 间质干细胞及急性肺损伤间质干细胞和急性肺损伤专业知识讲座第1页ARDS was first recognized in the 1960s1 as a clinical syndrome of severe acute respiratory failure presenting with hypoxemia and bilateral pulmonary infiltrates,most often in the setting of pneumonia,sepsis,or major trauma.lARDS最初在1960年，被人们认识为严重急性呼吸衰竭临床综合征；l血氧不足和双边肺浸润，通常继发于肺炎、败血症、或严重创伤；间质干细胞和急性肺损伤专业知识讲座第2页distinction between(ALI)and ARDS relates to the severity of hypoxemia,with the former having a PaO2/FiO2 of less than 300,the latter with a PaO2/FiO2 of less than 200.lung endothelial injury,alveolar epithelial injury,the accumulation of protein-rich fluid、cellular debris in the alveolar spacel急性肺损伤(ALI)和ARDS区分主要指血氧不足严重程度，前者有PaO2/FIO2小于300;l后者PaO2/FIO2不足200;lALI/ARDS发病机制包括肺血管内皮损伤,肺泡上皮损伤,富含蛋白质液体增加和肺泡腔内细胞残骸.间质干细胞和急性肺损伤专业知识讲座第3页流行病学流行病学l年,大约00名患者在美国发展为lALI/ARDS,预计有40%死亡率。l采取肺保护性通气时代,死亡率下降大约25%。l In,approximately 200,000 pts in the United States lALI/ARDS,with an estimated mortality of 40%.l In the era of lung protective ventilation,mortality has declined to approximately 25%.间质干细胞和急性肺损伤专业知识讲座第4页l大量临床试验,药品治疗吸入表面活性剂（inhaled surfactant）、一氧化氮（nitric oxide）、前列环素（prostacyclins）,糖皮质激素（glucocorticoids）,抗氧化剂（antioxidants）,酮康唑（ketoconazole）并非ALI治疗标准；lALI肺泡病理生理，任何单一分子不可能逆转综合症过程，使临床获益；l reverse the course of this syndrome、provide substantial clinical benefit.间质干细胞和急性肺损伤专业知识讲座第5页l细胞为基础疗法 cell-based therapies l能产生炎症分子 moleculesl调整炎症反应 modulate inflammatory cascades l增强修复 enhance repair l间充质干细胞可能是理想选择l Mesenchymal Stem Cells（MSC）间质干细胞和急性肺损伤专业知识讲座第6页间充质干细胞间充质干细胞:普通属性普通属性l间充质干细胞(msc)lself-renewing isolated from bone marrow differentiate into muscle,bone,fat,fibroblasts,and cartilage.l能重建造血环境 reconstitute a hematopoietic environment,regenerate bone tissue；l起初被称为成纤维细胞集落形成单位colonyforming unit-fibroblastic，(CFU-F)；l骨髓基质细胞marrow stromal cells,lMSC间质干细胞和急性肺损伤专业知识讲座第7页l依然不知道间充质干细胞是否来自中胚层,或者神经上皮,或来自不一样起源发展阶段lwhether MSCs originate from the mesoderm,from the neuroepithelium,or from different sourceslMSC 骨髓、脂肪,脐带血,胎盘组织、肌腱和骨骼肌、bone marrow、also from fat,umbilical cord blood,placental tissue,tendons、skeletal muscle 间质干细胞和急性肺损伤专业知识讲座第8页l国际上细胞治疗提出标准：l1.粘附整形adherence to plastic；l2.expression of CD105、CD73 CD90；lack of expression of CD45、CD34、CD14 CD11b,CD79a、CD19和人类白细胞抗原(HLA)II；l3.ability to differentiate into osteoblasts,adipocytes,and chondroblasts in vitro.成骨细胞、脂肪细胞、软骨细胞能力。间质干细胞和急性肺损伤专业知识讲座第9页lother properties l1.produce a wide variety of molecules,including hematopoietic factors,chemokines,and angiogenic factors,包含造血因子,趋化因子和血管生成素。l2.immunomodulatory effects l3.MSC 基因治疗载体,并帮助诱导、同种异体骨髓移植耐受性。l4.MSC在疾病潜伏期模型获益，克罗恩病、创伤性脑损伤、Crohn disease、traumatic brain injury。l5.several types of lung disease 间质干细胞和急性肺损伤专业知识讲座第10页MSCs IN LUNG DISEASE l博来霉素暴露小鼠肺纤维化、Bleomycin exposure fibrotic lung diseasel分离小鼠干细胞而且静脉注射，随即7天，肺损伤区域发觉外源性间充质干细胞存在，且细胞含有上皮细胞特征；l显著降低肺内胶原蛋白沉积，降低基质蛋白酶2和9表示；lreduced collagen deposition and expression of matrix metalloproteinases 2 and 9.间质干细胞和急性肺损伤专业知识讲座第11页l肺移植（lung engraftment.）：强大抗炎作用 antiinflammatory effects；lblocks increase in interleukin (IL)-1a，白介素1(IL)产生。间质干细胞和急性肺损伤专业知识讲座第12页lgreen fluorescent protein(GFP)标识MSC治疗博来霉素诱导6h小鼠，improved survivallGFP标识MSC，表示纤维细胞(fibroblasts),肌纤维细胞(myofibroblasts),type I and type II alveolar epithelial cells.间质干细胞和急性肺损伤专业知识讲座第13页 MSCs umbilical cord tissueintravenously bleomycin in mice；MSCs were identified 2 weeks inflamed portions of the lung。脐带组织干细胞，静脉应用于老鼠体内，2周内肺内发觉。MSC降低胶原蛋白及细胞信号转导分子（Smad2）浓度，表明这些细胞已经含有抗纤维化属性。间质干细胞和急性肺损伤专业知识讲座第14页lbronchopulmonary dysplasia,MSCs intratracheally rats exposed to prolonged hyperoxia.reduced apoptosis,myeloperoxidase activity,and collagen deposition,inflammatory molecules IL-6,tumor necrosis factor(TNF)-a,differentiated into type II alveolar epithelial cells,l支气管肺发育不良动物模型，长久氧过多暴露老鼠气管内注入干细胞，发觉能够显著降低细胞凋亡、髓过氧化物酶活性和胶原沉积，以及炎性分子il-6、肿瘤坏死因子(TNF)。另外,少数细胞分化成II型肺泡上皮细胞。间质干细胞和急性肺损伤专业知识讲座第15页一样试验也提醒能够提升存活率及运动耐量改进,和降低肺泡和肺血管损伤,以及肺动脉高压。类似试验间充质干细胞气管内给药，能够降低大鼠肺动脉高压,改进血管内皮功效。van Haaften and colleagues reported that intratracheal MSCs improved survival、exercise tolerance,and decreased alveolar and vascular lung injury,pulmonary hypertension间质干细胞和急性肺损伤专业知识讲座第16页lrat model emphysema MSC reduced emphysematous changes.lMSCs differentiated into type II alveolar epithelial cells.lMSCs have therapeutic effects in several models of lung disease.lantiinflammatory properties,mitigating the lung damage in ALI.l辐射引发老鼠肺气肿模型，间充质干细胞降低肺气肿形成，分化成II型肺泡上皮细胞；l在肺部疾病模型中有治疗作用，适合用于ALI。l 间质干细胞和急性肺损伤专业知识讲座第17页MSCs IN ANIMAL MODELS OF ALI AND SEPSIS:EVIDENCE OF BENEFICIAL EFFECTS 干细胞在急性肺损伤和脓毒症动物模型：有利证据干细胞在急性肺损伤和脓毒症动物模型：有利证据l脂多糖(LPS)用于ALI动物模型；l气道给予LPS，48h诱发中性粒细胞聚集，与微血管通透性增加相关；l在ALI中，经鼻腔注入LPS，MSC 4h后在外周血中显著增加。间质干细胞和急性肺损伤专业知识讲座第18页lThey next subjected irradiated mice with bone marrow reconstituted from GFP transgenic donors to intranasal LPS,and showed abundant GFP-positive cells in the lungs 3 weeks later.Some of these cells expressed cytokeratin,a marker of epithelial cells,whereas others expressed CD34,a marker of endothelial cells.l辐照骨髓抑制小鼠，骨髓重建鼻内植入GFP标识MSC，3w在肺部发觉GFP标识MCS。l一些细胞表示上皮细胞标识细胞角蛋白（cytokeratin）,而其它细胞表示CD34,内皮细胞标识。间质干细胞和急性肺损伤专业知识讲座第19页lsuggested that endogenous MSCs play an important role in repairing inflammatory damage following LPS.l内源性MSC在LPS诱导急性炎症反应修复中起主要作用。l在一些试验中，低于致死剂量辐照引发骨髓抑制，鼻腔内LPS产生类似组织学损伤，且支气管肺泡灌洗(BAL)中性细胞增多，1W后产生肺气肿。l表明缺乏内源性MSC后破坏正常修复过程。间质干细胞和急性肺损伤专业知识讲座第20页MSCs intravenously 30 minutes，3 days later in BAL total cell reduction decrease in inflammatory infiltrates,interalveolar septal thickening,and interstitial edema.气管内小鼠体内，静脉MSC 30min，3天能够发觉显著降低BAL中总细胞和中性粒细胞计数。组织学分析证实降低炎症浸润,小叶间隔增厚,间质水肿。间质干细胞和急性肺损伤专业知识讲座第21页 intraperitoneal LPS 1 mg/kg (a dose that causes minimal mortality),1 hour later infused MSCs or fibroblasts intravenously.MSCs,reduced lung neutrophils at 6,24,and 48 hours.腹腔注射LPS 1mg/kg(最小致死量),1h后静脉干细胞细胞或成纤维细胞l干细胞治疗6、24和48h后肺部N%及总数下降间质干细胞和急性肺损伤专业知识讲座第22页lMSC intratracheally to mice 4h，after 5 mg/kg LPS,（a dose significant mortality）.MSC-treated mice improved survival lPBS-treated mice:l 80%versus 42%48 hours,l 64%versus 18%72 hours.l间充质干细胞小鼠气管内给药，随即4小时5毫克/千克脂多糖气管内给药，（能够产生显著死亡率剂量）l干细胞治疗后小鼠改进生存l相对于PBS-治疗后老鼠:l80%和42%在48小时内,l80%对18%在72小时。间质干细胞和急性肺损伤专业知识讲座第23页lHistologic analysis at 48 hours revealed less hemorrhage and edema.Nonviable MSCs and fibroblasts did not replicate this effect,suggesting undifferentiated,viable MSCs were required to ameliorate LPS-induced ALI.lMSC经过肺水（lung water）,湿/干比（wet/dry ratio）,and BAL蛋白质浓度 BAL protein concentration 48h后组织学显示出血和水肿降低l 提醒未分化,有活性干细胞能够改进LPS诱导ALI。间质干细胞和急性肺损伤专业知识讲座第24页l在肠杆菌肺炎模型中 大肠杆菌诱导小鼠肺炎中。4h后,这些小鼠气管内注入MSC、PBS,或成纤维细胞。l经过BAL中性粒细胞计数衡量，干细胞显著降低了肺部炎症。lMSCs,PBS,or fibroblasts.MSCs reduced lung inflammation,as measured by BAL neutrophil count.间质干细胞和急性肺损伤专业知识讲座第25页l最近研究了盲肠结扎和穿刺(CLP)脓毒症小鼠模型。l6h后，MSC或NS 静脉注射，全部小鼠天天都有广谱抗生素治疗。lSix hours following CLP,MSCs were infused intravenously.All mice received daily broad-spectrum antibiotics.间质干细胞和急性肺损伤专业知识讲座第26页MSCtreated mice had decreased BAL cell counts and albumin、reduced inflammatory lung infiltrates and interstitial edema 28h.benefit of MSCs was not to the lungs,MSC-treated mice had reduced apoptotic kidney cells and improved serum creatinine.CLP results in severe systemic injury,as shown by 45%mortality at 28h.MSC treatment improved mortality by 50%.l干细胞治疗后小鼠肺泡灌洗液细胞计数和白蛋白降低。l28h炎症性肺部浸润,间质水肿减轻。l除肺部外、肾脏细胞凋亡降低,血清肌酐下降。l脓毒症全身性损伤,28h 45%死亡率。治疗后死亡率下降50%。间质干细胞和急性肺损伤专业知识讲座第27页lintravenous(IV)MSCs or control cells(heatkilled MSCs or skin fibroblasts)24h before or 1 hour after CLP in mice.lAnd broad-spectrum antibiotics.survival benefit for MSCs at 4 days.lower serum creatinine and kidney tubular injury scores,improved hepatic glycogen storage,and reduced transaminases,amylase,and splenic apoptosis,lsuggesting multiple beneficial systemic effects.IV MSC或控制细胞(热死亡细胞或皮肤成纤维细胞)前24h或1h后脓毒症小鼠模型中，广谱抗生素。l4d MSC治疗生存率显著提升，降低血清肌酐和肾小管损伤评分,改进肝脏糖原存放,降低转氨酶,淀粉酶、和脾细胞凋亡。l多系统性有益。间质干细胞和急性肺损伤专业知识讲座第28页MSCs IN ANIMAL MODELS OF ALI AND SEPSIS:POTENTIAL MECHANISMS 干细胞在急性肺损伤和脓毒症动物模型干细胞在急性肺损伤和脓毒症动物模型:潜在机制潜在机制lMSCs may exert their therapeutic effects in models of ALI and sepsis,and have discovered an increasing number of potential mechanisms.lIt is helpful first to consider the processes governing the production and removal of alveolar edema fluid.l急性肺损伤和脓毒症模型中,MSC发觉越来越多潜在机制。l首要原因为肺泡水肿液管理和去除。间质干细胞和急性肺损伤专业知识讲座第29页内皮渗透性、上皮通透性和肺泡液体内皮渗透性、上皮通透性和肺泡液体间隙间隙lincreased protein of the endothelial and epithelial barriers,and reduced(or insufficient)alveolar fluid clearance(AFC).lMSCs reduce the increase in endothelial permeability ALI.lBAL albumin and protein are commonly used as markers of lung endothelial permeability。l在肺泡水肿形成：l内皮蛋白质通透性增加；l上皮屏障破坏，l肺泡液体去除率下降。lMSC能够降低ALI内皮通透性。BAL中白蛋白和蛋白质含量通惯用作肺内皮通透性指标。间质干细胞和急性肺损伤专业知识讲座第30页lBAL albumin,total protein,and immunoglobulin M(IgM)were increased 3 days following intratracheal LPS.lThis increase was attenuated by MSCs given intravenously 30 minutes after the injury.lAngiopoietin-1 may help maintain adultvascular endothelial cells in a quiescent state,reduce permeability and promote endothelial cell survival lLPS注入气管内3天后肺泡灌洗液中白蛋白、总蛋白和免疫球蛋白M(IgM)增加。ALI静脉注射MSC 30min，能够减轻蛋白含量。l血管生成素维持血管内皮细胞处于静止状态，同事降低渗透性,促进内皮细胞存活。间质干细胞和急性肺损伤专业知识讲座第31页 MSCs produce Ang-1 further reduced BAL protein,albumin,and IgM。Ang-1 diminishing inflammatory cell influx and reducing plasma protein leakage into the alveolar space.l在未损伤老鼠中MSC促进血管生成素降低BAL蛋白,白蛋白,IgM水平。l推断MSC静脉注射入肺循环中，促使Ang-1在降低炎性细胞浸润,降低血浆蛋白渗漏。间质干细胞和急性肺损伤专业知识讲座第32页l静脉MSC，脓毒症小鼠体内28h能够降低肺泡灌洗液中白蛋白，提醒MSC能够降低脓毒症内皮通透性l老鼠给与大肠杆菌气管内注射，18h后肺泡灌洗液中白蛋白显著增加，不过损伤后4h，气管内注射MSC(但不包含成纤维细胞)，白蛋白显著降低。间质干细胞和急性肺损伤专业知识讲座第33页lBAL中蛋白质能够评定肺血管内皮通透性、上皮通透性,肺水含量。l ALI中肺泡上皮细胞通常内皮细胞屏障失去完整性。间质干细胞和急性肺损伤专业知识讲座第34页l When exposed to inflammatory cytokines (IL-1b,TNF-a,and interferon IFN-g),increased 500%.l MSCs protein reduced to control levels.l当暴露在强效炎性细胞因子(IL-1b,TNF-a,和干扰素(IFN),上皮细胞层蛋白质渗透率增加大约500%。l植入同种异体干细胞，蛋白质渗透性降低到控制水平。ALI中，MSC能够提升上皮屏障功效 间质干细胞和急性肺损伤专业知识讲座第35页lAFC is the capacity of the epithelium of the lung to remove alveolar fluid。lALI/ARDS can reduce AFC,including high tidal volume ventilation,live bacteria,acid instillation,and proinflammatory cytokines.l肺泡液体去除率（AFC），肺上皮细胞去除任何原因肺泡液体,肺水肿能力。lALI/ARDS中通常是（AFC）受损与恶化结果。l影响AFC原因：高潮气量、细菌,和促炎细胞因子l气管内注入MSC在ALI 4h后降低多出肺水。间质干细胞和急性肺损伤专业知识讲座第36页l体外肺灌注试验，用来测试MSC在ALI中效果。l LPS decrease in AFC,approximately 20%per hour to near 0%per hourl脂多糖造成肺泡液体去除率20%/h至0%/h。lfibroblasts into the injured lung 1h after had no effect on AFC.MSCs AFC to baseline levels.l成纤维细胞肺受伤1小时后应用，肺泡液体去除率没有影响。干细胞肺泡液体去除率至基线水平。间质干细胞和急性肺损伤专业知识讲座第37页lMSCs improve both endothelial/epithelial permeability and AFC。l所以,得出结论干细胞似乎改进内皮/上皮通透性和以及肺泡液体去除率。间质干细胞和急性肺损伤专业知识讲座第38页移植移植Engraftment lMSCs differentiate into bone,fat,muscle,cartilage。lin the late 1990s，these cells could develop a nonmesodermal phenotype.lMSC能够分化为骨,脂肪,肌肉,软骨；l1990年代末,在一定条件下,这些细胞能够发展为一个非中层表型。l标识干细胞融入博来霉素损伤后肺组织，表现出肺泡二型肺细胞形态学和分子特征。llabeled MSCs incorporated into lung tissue bleomycin injury and developed molecular characteristics of type I pneumocytes.间质干细胞和急性肺损伤专业知识讲座第39页llarge numbers of labeled MSCs in the lung 24h following IP LPS and IV MSC infusion.l2 weeks later,few labeled cells remained,presence of MSCs in the lung is a transient in ALI.l静脉注射脂多糖和静脉注入干细胞24h后，大量标识MSC在肺内发觉。l2周后,极少有标识细胞存在,这表明大量存在MSC在ALI中只是一个短暂现象。间质干细胞和急性肺损伤专业知识讲座第40页l对小鼠雾化脂多糖7天,第1天灌注入干细胞后，一些动物中,细胞能够表示Ang-1，输液后14天,标识细胞出现在肺内，但没有表现深入特征。Taken together,suggest that MSC differentiation into mature lung cell types following ALI may occur at low levels but is unlikely to produce much of their beneficial effect.l总而言之,数据表明,干细胞能够分化为成熟细胞，在ALI中可能发生在低水平,但不太可能产生有益效果间质干细胞和急性肺损伤专业知识讲座第41页免疫调整（免疫调整（Immunomodulation）lMSCs were recognized to have immunomodulatory effects，MSCs have suppress many functions of naive and memory T cells,B cells,natural killer (NK)cells,and the differentiation and function of monocytes lMSC抑制记忆T细胞、B细胞、自然杀伤(NK)细胞,单核细胞分化和功效。l脓毒症模型中气管内注入MSC能够使BAL中促炎细胞因子TNF-a和巨噬细胞炎性蛋白(MIP)2水平降低。增加抗炎细胞因子il-10、IL-1ra IL-13。间质干细胞和急性肺损伤专业知识讲座第42页l这些研究结果表明,在急性肺损伤中，干细胞能够促使肺环境从促炎到抗炎转变。lin a model of ALI shifts the injured lung from proinflammatory to antiinflammatory。l静脉注射MSC延缓脂多糖诱导ALI中血清促炎因子IFN-g，IL-1b，MIP-1a,KC；l脓毒症小鼠动物模型中，能够静脉注射MSC能够降低血清TNF-a和lL 6。间质干细胞和急性肺损伤专业知识讲座第43页lMSC治疗能够降低过氧物酶在脂多糖诱导小鼠脓毒症肝脏和肾脏中水平。lMSC治疗能够改进缺乏成熟T细胞和B细胞基因敲除小鼠，以及NK细胞缺点老鼠生存率。间质干细胞和急性肺损伤专业知识讲座第44页l在单核细胞和巨噬细胞缺点小鼠模型中，发觉MSC治疗没有效果,表明这些细胞经过干细胞治疗施加有益影响。l另外MSC被证实增加环氧酶表示和活性，增加前列腺素E2(PGE2)水平。l干细胞与巨噬细胞一起培养,脂多糖模型中发觉增加il 10，这种效果产生被证实依靠TLR4,MyD88 TLR4 NF-kB,TNF-a和TNF受体存在 间质干细胞和急性肺损伤专业知识讲座第45页l其它试验中,巨噬细胞反应经过EP2 PGE2和EP4受体。l在脓毒症中重组巨噬细胞分泌il 10激活干细胞,这降低了中性粒细胞迁移而且在组织中帮助减轻组织损伤。间质干细胞和急性肺损伤专业知识讲座第46页l据报道,脂多糖诱导脓毒症24h后,小鼠静脉治疗，多能干细胞(伤后6小时)降低血清促炎细胞因子,il-6、IL-1b KC，和趋化因子配体5(CCL5)，血清il-10也降低了,与原先试验中这种现象相反。l尚不清楚为何il 10在一个试验中增加，在另一个试验中降低,这可能与技术差异，MSC在损伤后应用时间相关。间质干细胞和急性肺损伤专业知识讲座第47页抗菌效果抗菌效果Antibacterial Effects lMSC除了能够有效抗炎效果，然而却显著改进由细菌引发败血症小鼠生存率。l试验表明,MSC能够降低细菌负担能力。l试验发觉，脓毒症小鼠模型中静脉注射脂多糖6h后，生存率极大改进。l比较损伤后28h脾脏细菌菌落数,MSC治疗组菌落数下降一个数量级别。间质干细胞和急性肺损伤专业知识讲座第48页在损伤后24h，分离了小鼠腹膜内和脾脏总细胞数或CD11b1片段(单核细胞/巨噬细胞和中性粒细胞)。lMSC治疗组增加了总细胞和CD11b1革兰氏阴性和革兰氏阳性细菌噬菌作用。lMSC本身极少从事吞噬作用,必须间接调整宿主吞噬细胞能力。间质干细胞和急性肺损伤专业知识讲座第49页l其它试验中，MSC一样含有抗菌性。l干细胞(比较成纤维细胞)降低大肠杆菌体外生长。间质干细胞和急性肺损伤专业知识讲座第50页lMSC条件培养基对G阴性菌生长没有影响,除非这些细胞原先被大肠杆菌细胞刺激,表明这种诱导产生抗菌物质。l他们筛选细菌刺激干细胞培养基发觉大量人类(LL-37)。l合成LL-37降低大肠杆菌和铜绿色假单胞菌生长，当与LL-37抑制性抗体同时培养时,受刺激MSC失去了抗菌活性。l老鼠脓毒症模型中，MSC治疗4h后,BAL显示细菌降低超出一个数量级，而使用LL-37抗体，抗菌效果却显著下降。间质干细胞和急性肺损伤专业知识讲座第51页lTaken together,the results suggest that MSCs both exert direct effects on bacteria and modulate the hosts phagocytic capacity.l Future experiments should help clarify the precise cellular and molecular pathways of phagocytic augmentation,and may identify additional direct antibacterial effects.l总来说,表明细胞对细菌起到直接作用和调整宿主噬菌作用能力。l未来试验应该深入说明确实切细胞、分子路径噬菌作用,和识别额外直接抗菌效果。间质干细胞和急性肺损伤专业知识讲座第52页其它可能机制其它可能机制Other Possible Mechanisms lMSC和组织细胞之间全新互动机制。l经过使用溴化乙锭改变DNA来减弱A549细胞线粒体功效。l这些细胞同MSC一起培养后，A549细胞取得了线粒体功效，且线粒体DNA同干细胞DNA相互匹配。l显微镜检提醒MSC能够逐步向A549细胞细胞质扩展，而且经过这种扩展使线粒体大量转运。间质干细胞和急性肺损伤专业知识讲座第53页l最近试验体外骨髓间充质向心脏肌细胞线粒体转移。l电子显微镜显示纳米管，线粒体能够经过纳米管转运。l线粒体能够经过囊泡、纳米管或一些其它机制转运，MSC能经过直接转移他们线粒体，主动挽救缺乏免疫力细胞，l线粒体缺点是许多器官损害模型共同特征，显示另一个潜在有益体内作用。间质干细胞和急性肺损伤专业知识讲座第54页l微泡被各种类型细胞释放,其中包含干细胞,同时微泡最近被认为是一个主要通信机制。l胚胎干细胞已被证实经过微囊泡重组造血祖细胞DNA。lMSC一样释放微泡。间质干细胞和急性肺损伤专业知识讲座第55页l最近研究表明，MSC能够诱导微泡增加肾小管上皮细胞在体外增殖,使得能够抵抗肾小管上皮细胞凋亡。l在严重免疫缺点小鼠,MSC及微囊泡有类似保护作用，抵抗甘油所致AKI。l在体内及体外试验中，核糖核酸酶能够消除这种主动效果，提醒这种效应是由间质干细胞DNA所产生。lMSC微囊泡与MRNA转录、增殖、免疫细胞监管相关。间质干细胞和急性肺损伤专业知识讲座第56页前瞻研究前瞻研究 FUTURE STUDIES l对MSC生物学功效还有待发觉。l未来工作将深入说明移植、免疫调整、抗菌效果,线粒体转移,遗传信息相关贡献。l缺乏可靠细胞表面标识极大地限制了这些细胞体内研究。l没有专门提供MSC基因敲除老鼠、没有详细MSC开启因子或免疫组织化学标识,以及怎样在体外骨髓寻找干细胞成为一个主要问题。间质干细胞和急性肺损伤专业知识讲座第57页lMSC越来越多广泛应用于临床。l当前干细胞正在研究用于急性心肌细胞梗塞,扩张性心肌病、克罗恩病、慢性阻塞性肺疾病、中风、多发性硬化症、移植物抗宿主病,急性I型糖尿病、糖尿病、糖尿病足溃疡、肝硬化和免疫重建综合症在人类免疫缺点病毒lacute myocardial infarction,dilated cardiomyopathy,Crohn disease,chronic obstructive pulmonary disease,stroke,multiple sclerosis,acute graft-versus-host disease,type I diabetes mellitus,diabetic foot ulcer,cirrhosis,and immune reconstitution syndrome in human immunodeficiency virus。间质干细胞和急性肺损伤专业知识讲座第58页lThe safety record for these cells has been reassuri