© 2010 Wichtig Editore - ISSN 2035-9969 Journal of Endometriosis ( 2010 ; : 2) 55-62 2 55 INTRODUCTION Early events in the natural history of endometriosis Endometriosis is a common disease, affecting a substan- tial fraction (10-15%) of menstruating women. The disease is characterized by the persistence and growth of vascula- rized endometrial tissue at ectopic sites, typically the pel- vis, with pain and reduced fertility (1-3, 4). According to the hypothesis originally put forward by Sampson, lesions ori- ginate from endometrial tissue shed during menstruation that reaches the abdominal cavity via the Fallopian tubes (5). Endometriosis does indeed occur exclusively in spe- cies that menstruate, including non-human primates, sug- gesting that menstruation is required for the disease (6). Innate immune cells: gatekeepers of endometriotic lesions growth and vascularization Annalisa Capobianco 1 , Lucia Cottone 1 , Antonella Monno 1 , Stefano Ferrari 2 , Paola Panina-Bordignon 3 , Angelo A. Manfredi 1 , Patrizia Rovere-Querini 1 1 Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute and Vita Salute San Raffaele University, Milan - Italy 2 Department of Gynecology and Obstetrics, San Raffaele Scientific Institute and Vita Salute San Raffaele University, Milan - Italy 3 Bioxell S.p.A, Milan - Italy Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute and Vita Salute San Raffaele University, Milan - Italy Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute and Vita Salute San Raffaele University, Milan - Italy Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute and Vita Salute San Raffaele University, Milan - Italy Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute and Vita Salute San Raffaele University, Milan - Italy ABSTRACT Infiltration by inflammatory leukocytes is a hallmark of all forms of endometriosis. Conversely, the innate immune system plays a key role in regulating events such as cell adhesion, migration, survival and neoangiogenesis of transformed or ectopic tissue. All these features are involved, and possibly required, in the development of endometriotic lesions. Recent data suggest that infiltrating leuko- cytes are not a mere epiphenomenon but represent an actual requirement for the development of the disease. In this scenario, the functional plasticity of infiltrating macrophages is a key event in the origin and maintenance of endometriotic lesions: the erroneous polarization of macrophages towards cells sustaining angiogenesis and tissue remodeling represents a potential target for novel molecular therapies. KEY WORD: Peritoneal lesions, Angiogenesis, Macrophages Accepted: April 23, 2010 Review According to this model, shed endometrium initially atta- ches to the surface of abdominal structures, including the peritoneal wall and ovaries (“adhesion step”). Adhesion of shed endometrial fragments to endo-abdominal structures is probably quite common even in healthy, non-endome- triotic women. At least in in vitro models, adhesion appears to occur in the relatively short time of 60 minutes (7). After adhesion, several coordinated events are required for the lesions to survive and spread. Necessary steps include invasion of the underlying basement membrane (“invasion step”), which occurs in the hours after adhesion. Peritone- al mesothelial cells apparently regulate and accelerate this event. Interestingly, in contrast with previous hypotheses, en- dometrial tissue invades intact membranes, suggesting that the previous disruption of the integrity of the peritoneal wall is not necessary and may not play a permissive role (8). FOR PERSONAL USE ONLY