Cell Stem Cell: 天津大学在化学重编程获得巨核细胞及血小板研究领域取得重要突破

2022-08-06 天津大学医学部 天津大学医学部

本研究有望为临床血小板短缺等问题开辟全新的解决途径。

2022年8月4日,天津大学医学部张健课题组联合军事医学研究院裴雪涛/李艳华团队在Cell Stem Cell在线发表文章,运用化学重编程技术实现了人成红细胞向巨核细胞及血小板的命运转换,并利用单细胞转录组和染色质开放性测序技术系统追踪了该过程中的细胞动态变化。基于干细胞技术、细胞重编程技术获取巨核细胞及血小板的研究一直是医学领域的国际前沿与热点,体外仅通过化学小分子介导的重编程技术制备人巨核细胞(血小板的前体细胞)及血小板的研究成果还鲜有报道,本研究有望为临床血小板短缺等问题开辟全新的解决途径。

血小板是由骨髓等造血组织中巨核细胞产生的具有生物活性的无核细胞,在机体止血、血栓形成、免疫调节、抗感染等生理和病理过程中发挥重要作用。临床上,血小板减少症常见于再生障碍性贫血、特发性血小板减少性紫癜等血液系统疾病,病毒/细菌性感染、创伤、急性放射病、肿瘤放化疗等也易引发血小板减少。血小板输注是临床治疗血小板减少症、防治出血、挽救生命的主要手段之一。目前血小板供应仅有健康志愿者捐献的唯一途径,而血小板贮存时间短且易被污染,遇到战争、重大自然灾害、突发公共卫生事件(如突发传染病)发生时,血小板短缺问题就会更加突出,因此亟需运用新技术解决血小板来源问题。

细胞重编程技术是2012年诺贝尔生理医学奖成果,它可在不改变基因序列的情况下,通过四个转录因子将成熟细胞重新编程成为类似胚胎干细胞,实现细胞命运转换,该技术现在被用于人体器官的再生等多个领域,具有巨大的临床应用潜能。在细胞重编程的研究中,种子细胞的选择对于能否成功而有效地启动细胞命运转换至关重要。前期研究表明,起始细胞和目的细胞在发育谱系上亲缘关系越近,越容易实现细胞类型转化。

成红细胞是存在于骨髓、外周血和脐带血中的一种有核红细胞,成红细胞和巨核细胞在发育过程中来自共同的前体,即巨核-红系共祖细胞,它们之间紧密的谱系联系使成红细胞成为获得巨核细胞理想的候选种子细胞。本研究通过从多个表观遗传调控和信号通路相关的小分子化合物中筛选出一个含有四个小分子的化合物组合,并惊奇地发现该小分子化合物“鸡尾酒”能将人成红细胞高效地重编程为巨核细胞。

本研究进一步确定了两阶段的诱导及巨核细胞特化的体系,最终获得了与天然巨核细胞特性相似的诱导性巨核细胞(induced megakaryocytes, iMKs)。巨核细胞最重要的功能是能产生前血小板及血小板。本研究首先通过体外实验分析iMKs是否具有生成血小板的能力。在体外特定诱导分化条件下,iMKs能够形成网状的具有多个分支延伸突起的前血小板并释放血小板。更为重要的是,实验表明iMKs来源的血小板表现出与天然血小板相似的凝血酶激活响应,并具有粘附、聚集等功能。为了确定iMKs是否具有体内生成功能性血小板的能力,将iMKs直接通过尾静脉注射到血小板减低症的免疫缺陷小鼠体内,在iMKs输注后的第1-3天检测到了人源性血小板,并通过微流控实验证实这些血小板具有参与血栓形成的能力。

为了解析四个小分子“鸡尾酒”如何实现成红细胞向巨核细胞的谱系命运转变,运用单细胞测序技术、染色质开放性测序技术对重编程过程进行了系统追踪和深度剖析。实验发现起始细胞经历了一个红系/巨核共前体细胞的阶段,该阶段的细胞具有红细胞及巨核细胞的双向分化潜能。进一步分析发现,该化合物组合引发了广泛的染色质重塑变化,红系细胞发育关键性基因的染色质开放程度逐渐降低,造血及巨核发生相关的重要转录因子基因位点的染色质开放程度逐渐升高,从而逐渐启动了巨核细胞发育程序。值得注意的是,本研究发现iMKs可以分为两个亚群,其中一个亚群为血小板生成偏向性强的巨核细胞,在iMKs总群体中的比例大于70%。另一个亚群是免疫偏向性的巨核系细胞,可能在免疫调节、炎症调节过程中发挥作用。四分子的重编程体系更有利于产生血小板生成偏向性强的巨核细胞。

综上所述,本研究独辟蹊径,仅运用小分子化合物成功实现成红细胞向功能性巨核细胞及血小板的命运转变,为体外大规模人工制备巨核细胞和血小板开辟了新的路径。该化学重编程技术具有安全可控、高效便捷等优势,通过该技术获得的功能性巨核细胞及血小板有望为临床血小板短缺等问题的解决开辟全新的途径,在血液系统疾病、急性放射病、战创伤、病毒或细菌性传染病等多种疾病引发的血小板减少症、出血的防治等方面展现出潜在的临床应用价值。

上述研究工作以“Direct chemical reprogramming of human cord blood erythroblasts to induced megakaryocytes that produce platelets”为题,在线发表于干细胞研究领域顶级期刊Cell Stem Cell上(影响因子25.269)。军事医学研究院裴雪涛研究员和李艳华研究员为该论文的共同通讯作者,军事医学研究院覃金华副研究员、天津大学医学部张健副教授以及军事医学研究院博士研究生姜佳楠是论文的并列第一作者。该研究得到国家重点研发计划和国家自然科学基金的支持和资助。

论文链接

https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00299-5

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