**2. Stem cells as the novel pathophysiology of endometriosis**

#### **2.1 Evidence of stem cell in the endometrium**

The presence of endometrium stem cells can be identified by the property of clonogenicity, side population cells, stem cell markers, multipotent cells, xeno-transplantation. Expression of pluripotent marker such as Oct-4, and the stem cell factor in ectopic endometrium suggest

Stem Cell as the Novel Pathogenesis of Endometriosis 265

The presence of the stem cell markers in the endometrium and endometriotic samples

Schwab & Gargett isolated mesenchymal stem-like cells from human endometrium in 2007 (Schwab & Gargett, 2007). They identified the endometrial stromal cells with the capacity of differentiated into cells of adipogenic, myogenic, osteogenic, and chondrogenic cell lineages. In the same year, the other research group (Wolff et al., 2007) also identified the chondrocytes from the human endometrium. These reports demonstrated the multipotent stem cells in the human endometrium. These multipotent endometrial stem/progenitor cells have reported to differentiate into 9 lineages: cardiomyocytic, respiratory epithelial, neurocytic, myocytic, endothelial, pancreatic, hepatic, adipocytic and osteogenic (Meng et

Some studies have demonstrated the formation of endometriotic lesion formation after transplantation of human endometrium into the immunodeficient mice such as severe combined immunodeficiency (SCID) and nude mice. Singly dispersed human endometrial cells were transplanted under the kidney capsules of non-obese diabetic (NOD)/SCID mice. They unveiled the reconstruction of endometrium by showing the formation of chimeric vessels, tortuous endometrial glands, tissue breakdown and bleeding (Masuda et al., PNAS 2007). Our previous investigation revealed the invasion and angiogenesis character after implanting with scaffolds seeded with eutopic or ectopic endometrial MSCs (Kao et al.,

Endometrium from the eutopic (inside the uterine cavity) or ectopic (outside of the uterine cavity), from the menstrual blood and bone marrow are the origin of the putative

**2.2.1 Isolation and culture of putative eutopic and ectopic endometrial mesenchymal** 

Endometrial stem cells can be cultivated from the endometrium epithelium and stroma. We isolated the putative eutopic and ectopic endometrial mesenchymal stem cells from the cases of endometriosis. According to our previous report (Kao et al., 2011), endometrial stromal cells were cultured from the tissue of eutopic and ectopic endometrium (from the endometrioma). At early passage (passage 5), endometrial stromal cells were seeded in triplicate at very low density (200 cells per 100 mm dish) in Dulbecco's modified Eagles's medium-Ham's F12 medium. After 21 days of incubation, large colonies were isolated and trypsinized into single cells. The diluted single cells were seeded in 96-well plates, clonally derived proliferating colonies were individually trypsinized and culture in a 100-mm dish after culture for 14 days. These isolated stem/progenitor cells illustrated the differentiation

suggest stem cell contributes to the pathogenesis of endometriosis.

**2.1.4 Multipotent cells identified in human endometrium** 

al., 2007).

2011).

**stem cells** 

**2.1.5 Xenotransplantation** 

endometrial stem cells.

**2.2 Source of the endometrium stem cells** 

that endometriosis has a stem cell origin (Pacchiarottic et al., 2011). There are two types of endometrium mesenchymal stem cells, one derived from the epitheilium and the other one from the stromal cells. The locations of these putative stem cells are supposed to be in the basalis of the endometrium (Figure 1). Some stem cell markers, for example, the RNAbinding protein Musashi-1 in colocalization with Notch-1 and telomerase increased in the basalis (Gotte et al., 2008). Recent study showed the endothelial progenitor/stem cells might reside in the endothelial cells (Maruyama et al., 2010). Some report showed the stem cell activity in endometrium through a stem cell niche with numbers of stem cells instead of a single stem cell (Kim et al., 2005). The function of endometrial stem cell/progenitor cell has be demonstrated to repair the damaged uterine surface in mouse model (Kaitu'u-Lino et al., 2010).
