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    Chairman's Research Description ( Hsin-Fu, Chen, M.D.)

  • 2013-08-16
  • In the past years, Dr. Chen continues the past research interests, focusing primarily on topics related to infertility treatment, human reproductive endocrinology, such as polycystic ovary syndrome (PCOS), embryonic development and human pluripotent stem cells, including human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. Firstly in 2004, under the supervision by Prof. Ho (Hong-Nerng Ho), Dr. Chen’s lab has derived 3 human ES cell lines of Taiwanese ancestry. These 3 cell lines had been well characterized about the morphology, growth speed, karyotypes, in vivo and in vitro differentiation potential, gene expression profiles and telomerase activity etc. Specifically these cells were proved to be capable of differentiating into germ cell lineage, including the development into ovarian follicle-like structures and the expression of germ cell markers, including VASA and SCP3 etc. This paper was published in Feb issue of Human Reproduction 2007 and the Figures in the paper was selected as the cover figures of this specific issue (please refer to figure). These studies confirmed that these human ES cell lines will be most useful cell for future pluripotent stem cell study. Dr. Chen’s lab is continuously working hard on this topic, and hopefully a useful experimental model, development from stem cells to germ cells, can be established for subsequent study on testing chemicals to improve human germ cell development and survival. Now further study on stem cell to germ differentiation by using a transgenic Oct4-eGFP H9 human ES cell line has been completed and the paper will be submitted within 2 weeks.         Additionally, to further improve the culture of human pluripotent stem cells using a more physiological and efficient way, we also tested the use of low oxygen tension in culture and checked its effect on the self-renewal, proliferation and in vitro differentiation potential of human ES cells. We found out that the hypoxic culture (O2 tension at 1-5%), in comparison to the standard normoxic culture (20% O2) maintains better morphology of the undifferentiated human ES cells after prolonged culture up to 14 days, improves the proliferation of the cells and increases the efficiency of differentiation of these stem cells to embryoid bodies (please refer to figure) These observations have been reported in high ranking journals including Human Reproduction 2009 and Tissue Engineering 2010. Subsequently from 2007, in collaboration with Dr. Kuo (Hung-Chih Kuo) in Academia Sinica, we started to derive and differentiate mouse and human iPS cells. Firstly we use cell surface markers including E-cadherin and Epithelial-cell-adhesion-molecule to isolate optimal mouse iPS cells originated from fibroblasts. We published this paper in Stem Cell Rev (2011). This specific study established the basic techniques needed for this Lab to derive human iPS cells. These human stem cell studies included the derivation of Pompe disease-specific human iPS cells (published by Dr. Huang HP in Hum Mol Genet 2011) and the premature ovarian failure (POF) patient-specific human iPS cells, recently derived in this Lab. We observed that this POF-specific iPS cells can develop to early germ cells, ovarian follicle-like structures, and functional ovarian granulose-like cells. However the efficiency and timing of granulose cell formation differ from those of “normal” human ES or iPS cells, suggesting the differential capabilities of diseased iPS cells. This POF-specific iPS cell likely will become an important cell model for studying germ cell and granulose cell development . (please refer to figure)   We will soon submit this manuscript to report these important findings. Using the same model for study, we are also using granulose cells from PCOS (a very common female endocrine disorder) patients to derive human diseased iPS cells, in order that we can study this important human disease more thoroughly and hopefully to identify useful chemicals or drugs for treating this disease. About the detailed study of human stem cells to granulose-like cells, we have published an efficient protocol to differentiate human pluripotent stem cells first to mesodermal lineage, and then to human granulose-like cells. We proved that these granulose-like cells retain the characteristic gene expression profile (including AMH, AMH-R, FSH-R, aromatase etc.) of human granulose cells. We also showed that these granulose-like cells are functional, since they were able to convert androgens to estradiol, suggesting the presence of functional aromatase enzyme. Again this model is extremely useful for studying steroid hormone-producing cells and for drug testing. This related study has already been published in J Clin Endocrinol Metab 2013. (please refer to figure) Since immune response is one of the major issues related to the successful use of stem cell derivatives for transplantation, we have worked hard on the immunogenicity of human iPS and ES cells and their derivatives. We found out that always these cells are immunogenic, they retain certain levels of immune privilege which are likely regulated by several important genes. One paper related to this issue is undergoing revision in Cell Transplantation and the other paper will be submitted soon . (please refer to figure)   Dr. Chen’s Lab is actively continuing the important research work related to the topics described above. We hope and have good confidence that these works will provide useful data to improve human translation medicine, and specifically to improve human reproductive health. ...
  • Post source:基蛋所BLOG


  • 2013-07-23
  •     過去數年以來,陳信孚醫師的研究仍持續過去的主要項目:其中包括不孕症、人類生殖內分泌,如多囊性卵巢症候群的研究、人類胚胎之發育、以及人類多能幹細胞,包括人類胚胎幹細胞與誘導型多能幹細胞之研究。   首先於2004年,在何弘能教授的指導之下,陳信孚醫師的實驗室已建立了3株源於國人血源之人類胚胎幹細胞株。這3株幹細胞皆經過詳細的檢驗,包括型態、生長速度、染色體、體內與體外之分化能力、基因表現等等,證實其為人類幹細胞研究之重要素材。尤其是這幾株幹細胞被證實具有發育為人類生殖細胞之潛能,包括發育為類似卵巢濾泡之構造以及表現出生殖細胞之基因,包括VASA與SCP3等等,相關論文發表於2007年2月份之「人類生殖」雜誌,文章的圖片並被選為該期雜誌之封面 (詳見圖片) 這一部份的研究我們正持續進行當中,最近我們進一步使用一株轉殖基因Oct4-eGFP H9人類胚胎幹細胞株,來分化成為生殖細胞,這部分的研究已經完成,論文也將在兩星期內投稿。(詳見圖片)   另外我們在培養幹細胞過程中也持續探討低氧氣濃度之培養環境,探討其對於這些人類多能幹細胞之自我增生、增加數目、體外分化能力的影響。我們發現使用較低的氧氣濃度可以有效維持人類胚胎幹細胞於更好的未分化型態、更強的增生能力、以及形成類胚體的效率更加提高,這一部份的研究也已發表於2009年「人類生殖」雜誌,以及2010年「組織工程」雜誌。(詳見圖片)   之後2007年,我們與中研院郭紘志博士合作,開始嘗試小鼠以及人類誘導型多能幹細胞之建立與分化。首先我們以E-cadherin以及Epithelial-cell-adhesion-molecule兩種細胞膜表面標誌,來選擇出最好的小鼠誘導型多能幹細胞,這個論文已發表在Stem Cell Rev. (2011)。這個研究為我們建立人類誘導型多能幹細胞(iPSCs)立下良好的基礎,這些人類誘導型幹細胞包括我們與中研院的團隊合作建立的龐貝氏症人類誘導型多能幹細胞(由黃祥博博士發表於Hum Mol Genet, 2011),以及我們也已建立了人類卵巢早發衰竭患者之特異性之人類iPSCs,我們發現這一株患者之iPSCs可以在體外發育為初期的生殖細胞,以及卵巢的顆粒細胞,但是我們發現這一株病患特異之幹細胞發育成顆粒細胞的時間與效率與一般正常人的iPSCs並不一樣,代表這種卵巢早發衰竭患者之iPSCs,確實可能具有卵巢發育之特異性,因此對於我們用來當作一種疾病的模式以及測試促進卵巢發育或保存之藥物或毒物的測試,都有高度的潛能。這一部份的論文我們也已完成即將投稿。(詳見圖片) 使用同樣的研究模式,我們也正在使用多囊性卵巢症候群患者的顆粒細胞,來建立人類iPSCs,由於多囊性卵巢症候群是一種婦女非常常見的疾病,因此建立這類患者之iPSCs,將對於我們研究這種疾病,以及找出適當的藥物來治療這種疾病會有重大貢獻,這部份的研究正在積極進行當中。   另外關於人類多能幹細胞發育成為卵巢顆粒細胞之研究,我們已經發表第一手研究報告,證明我們可以把人類胚胎幹細胞以及iPSCs,有效的經過中胚層細胞的發育,然後發育成為類似卵巢顆粒細胞,這些細胞表現出顆粒細胞該有的基因表現,同時它具有把男性荷爾蒙轉化成為女性荷爾蒙的功能,證實此種細胞帶有Aromatase觸媒,所以確實非常接近顆粒細胞的型態與功能,因此這樣的發育模式,同樣對於研究荷爾蒙細胞之調節、藥物與毒物測試都有高度的價值,這一部份的研究我們已於本年發表於J Clin Endocriol Metab (2013)。(詳見圖片) 此外關於多能性幹細胞之發育產物是否可以有效做為細胞移植之素材,顯然這些細胞之免疫特性非常重要。近兩年來我們已深入探討這一個議題,發現這些人類多能幹細胞以及其產物,雖然很可能會造成免疫排斥,但是他們也具有一定程度的免疫特權(immune privilege),而且有一些基因的表現對於這些免疫特權的表現具有調節的功能;顯然研究這些特殊的基因對於這些幹細胞的產物,未來使用於細胞移植將有重要的價值,這部份的研究我們也正投稿當中。(詳見圖片)   因此陳信孚醫師的實驗室正執行長期連貫性的研究,著重在胚胎、生殖內分泌、人類多能幹細胞之相關研究,許多具有臨床價值與科學意義的成果與論文,將在這數年內陸續發表出來。 ...
  • Post source:基蛋所BLOG
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