幹細胞於生殖醫學之發展及應用

Development and Application of Stem Cell Technology in Reproductive Medicine

人類幹細胞分兩大類：一類為成體幹細胞；另一類是多能性幹細胞，包括胚胎幹細胞（ESCs）與誘導型多能幹細胞（iPSCs）。這兩類多能性幹細胞皆具有分化為體內各式細胞，包括生殖細胞的能力。由於人類的生命要能夠延續，必須生殖細胞（包括卵子與精子）確實能執行其生育功能：也就是男性能產生足夠數量、濃度、活動力、且正常形態的精蟲；而女性也必須產生足夠數量且品質優良的卵子。之後這些精蟲與卵子還要達成精卵受精成為胚胎，最後胚胎能著床於子宮並發育為正常胎兒的過程。如此胎兒出生之後一代一代傳承，使人類生命得以延續。然而在現實世界裏，有些配偶並不易受孕，因此需要借助人工協助生殖技術（ART），包括人工授精或試管嬰兒（IVF）來達成，這就是生殖醫學的主要任務。然而即使有這些技術，有些不孕症患者還是無法成功受孕，主要的原因是卵子或精子的缺乏或品質不佳。例如有些婦女罹患卵巢早發衰竭的病症，卵巢沒有排卵功能，沒有卵子來進行人工生殖技術，而必須借助別人捐贈卵子，但這畢竟不是所有患者都可以接受，而且精卵的來源也常有匱乏。因此我們研究如何建立人類胚胎幹細胞與誘導型多能幹細胞，以及培育這些多能幹細胞成為生殖細胞的技術與細胞模式，除了有科學上的意義之外，實則在生殖醫學領域上，有可能可以用來治療包括不孕症、習慣性流產與早發性卵巢衰竭等疾病。此外最近數年來，科學界最大的突破點是一種號稱為「萬能細胞」（誘導型多能幹細胞；iPSCs）的發明，這種細胞可以由患者身上的體細胞，在實驗室中鑲入數個轉錄因子之後，培養成類似人類胚胎幹細胞特性的細胞。由於iPSCs 之DNA 基本上與患者本身是一樣的，因此由iPSCs 培育成的卵子是量身訂作，患者專屬，可以回過頭來用於解決自己的不孕症問題。最近我們除了更有效率的把多能性幹細胞發育為早期生殖細胞之外，並進一步也把幹細胞發育成為卵巢的間質細胞，包括卵巢顆粒細胞。同時我們還把一位卵巢早發衰竭患者身上的皮膚細胞，建立其個人專屬的誘導型多能幹細胞，並把這些細胞也同樣發育成早期生殖細胞與顆粒細胞，因此我們初步證明，這些多能性幹細胞確實在生殖醫學上將會有促進其發展與未來應用的重大潛能。

There are two major types of human stem cells, adult stem cells and pluripotent stem cells. The latter usually include embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). It is clear that human life can be extended forever only when gametes (oocytes and sperm) can function in efficient ways. Practically the gametes need to be optimal about quantity and quality, should be capable of achieving fertilization, can develop into good embryos for final implantation into the uterus, and finally develop into viable fetus in the uterus. However in real life, a certain percentage of couples actually cannot achieve pregnancy without resorting to assisted reproduction. In recent years the use of assisted reproduction including in vitro fertilization (IVF) has help a big number of infertile couple to achieve pregnancy. However, some couples still fail to get pregnant even after the use of IVF, principally due to the poor gamete quantity or quality. For example, some women may encounter premature ovarian failure/insufficiency before the age of 40 and therefore may finally need oocyte donation program to achieve pregnancy. For this subgroup of patients, stem cell technology may become a potentially useful tool for these patients. Actually the current trends are that the techniques of assisted reproduction have been extended more than just to assist couples for pregnancy. For example, the embryos produced by IVF can be manipulated in vitro to derive human ESC and patient-specific human iPSCs can be produced simply by obtaining skin fibroblasts from the patients and going through some routine lab procedures. In recent years, we and a number of international researchers are working on deriving human ESC and iPSCs and also on differentiating these stem cells into cells of interest, including cardiomyocytes, hepatocytes and also germ cells. Hopefully the derivation of patient-specific pluripotent stem cells and subsequent germ cell and related cells (for example ovarian granulosa cells) can be useful as models of studying germ cell formation, testing chemicals or drugs for regulating germ cell development, and finally to produce mature germ cell for cell therapy purpose. Therefore it is becoming clear stem cell technology has opened a new avenue towards more efficient way to improve the efficiency of reproductive medicine.