Human endometrium is a proliferative, angiogenic, and dynamically regenerated normal tissue that is the anatomic prerequisite for pregnancy [1
]. At menses and postpartum the endometrium exhibits a proinflammatory environment, extensive extracellular matrix remodeling, vasospasm, hypoxia, cell death, and tissue desquamation, with wound repair mechanisms and cellular proliferation and differentiation participating in its regeneration without scarring [2
]. Stem/progenitor cells (epithelial, mesenchymal, endothelial) likely contribute to the rapid endometrial cyclic growth and regeneration of 4–14 mm of mucosa per cycle during the more than 400 cycles in a woman's reproductive lifespan and endometrial regeneration/repair postpartum [6
]. It is well known that bone marrow-derived mesenchymal stem cells (MSCs) in the circulation can home to sites of damaged tissues [9
], and it has been postulated that bone marrow-derived MSCs participate in cyclic endometrial repair and regeneration and may be progenitors of stromal fibroblasts and perhaps epithelial cells in the endometrium [7
]. The phenotype of the stem/progenitors, what regulates their potential homing to endometrium, and mechanisms underlying their roles in endometrial tissue regeneration remain unresolved and are the subject of much investigation [6
Stem cells in adult tissues are primarily quiescent, although they have enormous capacity to proliferate to achieve self-renewal (proliferation and maintenance of the undifferentiated state), and they also exhibit multipotency, differentiating along tissue-specific lineages and migrating within the tissue and replenishing their tissue constituents [10
]. Mesenchymal stem cslls share these properties, are self-renewing, and differentiate in vitro and in vivo along chondrogenic osteogenic, adipogenic, myogenic, and tenogenic lineages [13
]. In addition, they exhibit immunomodulatory properties [17
]. Recently, a small population of clonogenic, self-renewing, multipotent MSCs with high proliferative potential has been identified in human endometrium [20
]. The endometrial MSCs (eMSCs) coexpress melanoma cell adhesion molecule (MCAM; also known as cluster of differentiation 146 [CD146]) and beta-type platelet-derived growth factor receptor (PDGFRB) surface markers [6
] and have a perivascular location [21
]. These eMSCs likely represent the reservoir of progenitors giving rise primarily to the stromal fibroblast lineage [23
], which is also of mesenchymal origin. Recent studies using animal transplantation models are consistent with eMSC differentiation to the stromal fibroblast [24
], supporting a common lineage of eMSCs and endometrial stromal fibroblasts.
Gene expression profiling has provided insights into molecular pathways involved in bone marrow and adipose MSC self-renewal and maintenance of multipotency [13
], and despite interest in the potential use of these MSCs in regenerative medicine [25
], little is known about the genetic program of eMSCs. In this context, in the present study we prospectively isolated highly purified MCAM (CD146)+
eMSCs and report their clonogenic potential, multipotency, and perivascular location in adult human endometrium. Expression profiling results reveal that eMSCs have a phenotype consistent with self-renewal, multipotency, immunomodulation, and homing, and support a common lineage for eMSCs and endometrial stromal fibroblasts. Furthermore, as pericytes, the cells are well positioned to migrate into the stroma and differentiate and regenerate endometrial tissue when signaled by tissue breakdown processes, and their genetic program suggests they have the capacity to respond to tissue and matrix proteolysis, tissue hypoxia, inflammation, desquamation, and wound healing.
Understanding the biology of endometrial stem cell populations is important for defining normal and abnormal endometrial tissue regeneration and lineage cell commitment. Transmission of abnormalities across cell lineages may contribute to proliferative disorders, such as endometrial polyps, endometriosis, and endometrial hyperplasia/cancer; adenomyosis; and compromised interactions of lineage cells with the conceptus/placenta, contributing to infertility, implantation failure, or poor pregnancy outcomes. The genetic program of eMSCs described in the present study provides a fundamental understanding of pathways involved in self-renewal and multipotency, and candidate genes regulating the repair, regeneration, and function of human endometrium.