造血干细胞研究发展历史引发的思考

Adjunctive Reflections on History of Hematopoietic Stem Cell Study--Editorial

本文简要地回顾了世界干细胞研究数十年的历史经过。它的原始研究是为了解决二次大战末在日本两次核爆炸中所见的致死性造血损伤,这也说明世界干细胞研究为什么从造血干细胞开始,而且人们长期不关心非造血干细胞在体内是否存在。20世纪50-60年代一些聪明设计的动物实验有力地暗示造血干细胞在体内的存在,动物研究又证实正常骨髓可以修复已严重破坏的骨髓,于是人们开始相信骨髓移植就是造血干细胞移植。培养造血祖细胞集落的陆续发现证明造血祖细胞的存在。直至上世纪90年代,有了NODSCID或羊胎等体内检测造血干细胞的可靠方法之后,才划清了造血干细胞和祖细胞的界限。本文列举了许多实例,说明实验血液学和临床血液学发展的互动性,以及其它生物学和技术的进步,尤其是免疫学和分子生物学的进步,极大地推动了干细胞基础研究和临床干细胞移植的发展。比如HLA、单克隆抗体、DNA分子克隆、基因重组工程技术以及近年发展的生物信息学、基因组学、蛋白质组学、干涉RNA、干细胞工程技术等,使干细胞基础和临床研究进入了21世纪的新时代。免疫治疗、间充质干细胞和干细胞工程的发展,结合用于造血干细胞移植,使细胞治疗多元化成为本世纪发展的新动向。本文着重地介绍了干细胞研究的每一步发展都同时出现认识上的误区,以及给干细胞研究带来了挫折。一个误区的澄清常常历时20甚至40多年之久。例如造血干细胞与祖细胞的区分;造血干细胞体外扩增研究在世界各国注定的失败;移植脐血缺乏的是造血干细胞,还是祖细胞;多数白血病是否起病于造血干细胞;以造血干细胞是否是基因治疗中最佳的外源基因载体;又如干细胞工程能否克隆实质脏器等等。在成体组织内存在成体干细胞是21世纪划时代的伟大发现,却也带来了误区和风波。本文重点分析了在成体干细胞发现的同时为什么会出现横向分化、去分化等缺乏科学根据的假说,以及部分同行视线混乱的根源与教训。文章指出误区的发生是由于缺乏实践和认识的片面性造成的,科学实践是检验和纠正认识片面性的唯一途径。整个干细胞研究的发展历史正是一个不断纠正认识误区的过程,也是必由之路。

The article reviews concisely around the history of hematopoietic stem cell research, basic and clinical, since its very beginning after the nuclear explosions at the end of the Second World War, that explains why the stem cell study in the world began with the hematopoietic stem cells and the existence of non-hematopoietic stem cell in vivo had been left out of account for many decades till 21 st century. During 50 -60s of the last century, it was known from the animal experiments that there must be hematopoietic stem cells existing in vivo and believed that the effective bone marrow transplant is actually the stem cell transplantation. It is reviewed how the basic studies of stem cell interacted with the clinical stem cell transplantation and how great the contribution was given to strongly push forward the development of contemporary stem cell biology and modern hematology from the basic studies especially in the immunological and molecular biological fields, for instance, the applications of HLA technology and monoclonal antibody produced, flow cytometry, and genetic recombinant cytokines, the novel technique for gene cloning, genomics, proteomics, and iRNA as well as bioinformatics. It has lead to the pluralistic cell therapy as a novel trend in stem cell transplantation as to combine immunotherapy and mesenchymal stem cells with the conventional stem cell transplants. This paper looks back in the past several decades, however, on every achievement of stem cell study that were usually accompanied with some idealistic one-sidedness or even errors in design and conclusion of some experiments. Usually it took a period of 2 or even 4 decades to clarify some basic idea, that seemed normal in the science development, for examples, the dividing line between the hematopoietic stem cell and progenitor cells, possibility to expand or clone the real stem cell ex vivo, and whether the majority of leukemias are originated from stem cell level, etc. Towards the end of 20th century, the greatest discovery was the existence of adult stem cells in adult tissues, which are no doubt the remnants from the embryonic development including all stages of embryonic stem cells, very earlier and later, hematopoietic and nonhematopoietic, and could be induced to differentiate into all kinds of tissue cells by proper ways in vitro. No evidence has really provided for the hypothesis of so called trans-differentiation or de-differentiation, which brought about strong calls in questions in the past 5 years. The problems in developing the clinical gene therapy by using hematopoietic stem cell as carrier of interested gene still remained to be solved so far. Because of the relatively weak base of related basic studies, the clinical application of gene therapy resulted in the failure of clinical practice with lots of lessons towards the end of last century. The whole history of stem cell study in the world was an endless process of continuous redress for theoretical ideas in stem cell biology that had never been consummate.