Grant-in-Aid for Scientific Research (A)
|Allocation Type||Single-year Grants |
Obstetrics and gynecology
|Research Institution||Keio University |
YOSHIMURA Yasunori Keio University, School of Medicine, Professor, 医学部, 教授 (10129736)
OKANO Hideyuki Keio University, School of Medicine, Professor, 医学部, 教授 (60160694)
MARUYAMA Tetsuo Keio University, School of Medicine, Assistant Professor, 医学部, 講師 (10209702)
TANAKA Mamoru Keio University, School of Medicine, Assistant Professor, 医学部, 講師 (20207145)
MATSUZAKI Yuki Keio University, School of Medicine, Associate Professor, 医学部, 助教授 (50338183)
UCHIDA Hiroshi Keio University, School of Medicine, Instructor, 医学部, 助手 (90286534)
清水 亜紀 慶應義塾大学, 医学部, 助手 (60306826)
|Project Period (FY)
2002 – 2004
Completed (Fiscal Year 2004)
|Budget Amount *help
¥41,860,000 (Direct Cost: ¥32,200,000、Indirect Cost: ¥9,660,000)
Fiscal Year 2004: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2003: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
Fiscal Year 2002: ¥28,210,000 (Direct Cost: ¥21,700,000、Indirect Cost: ¥6,510,000)
|Keywords||endometrium / myometrium / stem cells / differentiation / regenerative medicine / 子宮筋 / 免疫不全マウス / DNAマイクロアレイ|
The objective of this study was to identify and isolate adult stem cells (tissue-specific stem cells) from the female reproductive tract and to search for their application to the regenerative medicine.
1.Isolation of tissue-specific stem cells from the female reproductive tract and functional analysis of their stem cell potentials
a)Endometrial stem cells
A highly regenerative potential of the human endometrium strongly suggests the existence of endometrial stem cells. Dual-wavelength flow cytometric analysis of cells isolated from a variety of tissues has shown that Hoechst 33342 dye exclusion is able to define a side population (SP) of stem cells relevant to target tissues, suggesting that SP is a universal stem cell phenotype. We found that endometrial side population cells (ESP) existed in the human endometrium throughout the menstrual cycle. Isolated ESP reconstituted not only functional endometrium-like tissues with glandular structures but also various endometrial components when
transplanted into severely immunodeficient mice.
b)Myometrial stem cells
Uterine smooth muscle (myometrium) undergoes profound tissue remodeling together with marked hypertrophy and hyperplasia during pregnancy, suggesting the existence of myometrial stem cells. We found that myometrial SP cells (MSP) were present in the non-pregnant human myometrium. Isolated MSP were quiescent and possessed a potential to differentiate into other cell-lineages including adipocytes and osteocytes. Furthermore, xenotranplantation experiments revealed that MSP, but not non-MSP, reconstituted myometrium-like tissues in vivo.
Several genes selectively expressed in ESP and MSP were so-called stem cell markers such as ABCG2. Thus, we for the first time isolated ESP and MSP from the female reproductive tract and identified them as putative endometrial and myotmetrial stem cells, respectively.
2.Regulation of endometrial differentiation
Data on the regulation of differentiation of the female reproductive tissues is necessary for clinical application of their tissue-specific stem cells to regenerative medicine. We demonstrated that histone acetylation and Src-mediated signaling pathways were required for endometrial cell differentiation. Furthermore, we successfully modified endometrial differentiation by targeting those pathways using low molecular weight chemicals. Less