title: Autologous cell therapy with CD133+ bone marrow-derived stem cells for refractory Asherman's syndrome and endometrial atrophy: a pilot cohort study.
abstract: OBJECTIVE
  Could cell therapy using autologous peripheral blood CD133+ bone marrow-derived stem cells (BMDSCs) offer a safe and efficient therapeutic approach for patients with refractory Asherman's syndrome (AS) and/or endometrial atrophy (EA) and a wish to conceive?
  
  
  CONCLUSIONS
  In the first 3 months, autologous cell therapy, using CD133+ BMDSCs in conjunction with hormonal replacement therapy, increased the volume and duration of menses as well as the thickness and angiogenesis processes of the endometrium while decreasing intrauterine adhesion scores.
  
  
  BACKGROUND
  AS is characterized by the presence of intrauterine adhesions and EA prevents the endometrium from growing thicker than 5 mm, resulting in menstruation disorders and infertility. Many therapies have been attempted for these conditions, but none have proved effective.
  
  
  METHODS
  This was a prospective, experimental, non-controlled study. There were 18 patients aged 30-45 years with refractory AS or EA were recruited, and 16 of these completed the study. Medical history, physical examination, endometrial thickness, intrauterine adhesion score and neoangiogenesis were assessed before and 3 and 6 months after cell therapy.
  
  
  METHODS
  After the initial hysteroscopic diagnosis, BMDSC mobilization was performed by granulocyte-CSF injection, then CD133+ cells were isolated through peripheral blood aphaeresis to obtain a mean of 124.39 million cells (range 42-236), which were immediately delivered into the spiral arterioles by catheterization. Subsequently, endometrial treatment after stem cell therapy was assessed in terms of restoration of menses, endometrial thickness (by vaginal ultrasound), adhesion score (by hysteroscopy), neoangiogenesis and ongoing pregnancy rate. The study was conducted at Hospital Clínico Universitario of Valencia and IVI Valencia (Spain).
  
  
  RESULTS
  All 11 AS patients exhibited an improved uterine cavity 2 months after stem cell therapy. Endometrial thickness increased from an average of 4.3 mm (range 2.7-5) to 6.7 mm (range 3.1-12) ( ITALIC! P = 0.004). Similarly, four of the five EA patients experienced an improved endometrial cavity, and endometrial thickness increased from 4.2 mm (range 2.7-5) to 5.7 mm (range 5-12) ( ITALIC! P = 0.03). The beneficial effects of the cell therapy increased the mature vessel density and the duration and intensity of menses in the first 3 months, with a return to the initial levels 6 months after the treatment. Three patients became pregnant spontaneously, resulting in one baby boy born, one ongoing pregnancy and a miscarriage. Furthermore, seven pregnancies were obtained after fourteen embryo transfers, resulting in three biochemical pregnancies, one miscarriage, one ectopic pregnancy, one baby born and one ongoing pregnancy.
  
  
  CONCLUSIONS
  Limitations of this pilot study include the small sample size and the lack of control group.
  
  
  CONCLUSIONS
  This novel autologous cell therapy is a promising therapeutic option for patients with these incurable pathologies and a wish to conceive.
  
  
  BACKGROUND
  This study was funded by the Spanish Ministry of Science and Innovation (SAF 2012-31017, Principal Investigator C.S.), Spanish Ministry of Health (EC11-299, Principal Investigator C.S.) and Regional Valencian Ministry of Education (PROMETEOII/2013/018, Principal Investigator C.S.). Four authors (X.S., I.C., A.P. and C.S.) are co-inventors of the patent resulting from this work (Application number: 62/013,121). S.C., C.A., F.R., J.F., J.P. and J.R. have no conflict of interest in relation to this work.
  
  
  BACKGROUND
  This study was registered with ClinicalTrials.gov (NCT02144987).
authors.affiliation: Fundaciœn Instituto Valenciano de Infertilidad (FIVI), Department of Obstetrics & Gynecology, School of Medicine, Valencia University and Instituto Universitario IVI/INCLIVA, Valencia, Spain Instituto Valenciano Infertilidad (IVI) Barcelona, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Santamaria
authors.affiliation: Instituto Valenciano Infertilidad (IVI) Valencia, Valencia, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Cabanillas
authors.affiliation: Fundaciœn Instituto Valenciano de Infertilidad (FIVI), Department of Obstetrics & Gynecology, School of Medicine, Valencia University and Instituto Universitario IVI/INCLIVA, Valencia, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Cervelló
authors.affiliation: Department of Hematology, Hospital ClÚnico Universitario/INCLIVA, Valencia, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Arbona
authors.affiliation: Department of Obstetrics & Gynecology, Hospital ClÚnico Universitario/INCLIVA, Valencia, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Raga
authors.affiliation: Instituto Valenciano Infertilidad (IVI) Valencia, Valencia, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Ferro
authors.affiliation: Department of Radiology, Hospital ClÚnico Universitario/INCLIVA, Valencia, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Palmero
authors.affiliation: Fundaciœn Instituto Valenciano de Infertilidad (FIVI), Department of Obstetrics & Gynecology, School of Medicine, Valencia University and Instituto Universitario IVI/INCLIVA, Valencia, Spain Instituto Valenciano Infertilidad (IVI) Valencia, Valencia, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Remohí
authors.affiliation: Fundaciœn Instituto Valenciano de Infertilidad (FIVI), Department of Obstetrics & Gynecology, School of Medicine, Valencia University and Instituto Universitario IVI/INCLIVA, Valencia, Spain Instituto Valenciano Infertilidad (IVI) Valencia, Valencia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pellicer
authors.affiliation: Fundaciœn Instituto Valenciano de Infertilidad (FIVI), Department of Obstetrics & Gynecology, School of Medicine, Valencia University and Instituto Universitario IVI/INCLIVA, Valencia, Spain Instituto Valenciano Infertilidad (IVI) Valencia, Valencia, Spain Department of Obstetrics & Gynecology, Stanford University School of Medicine, Stanford University, Stanford, California Igenomix, Parc Cientific Valencia University, Paterna, Valencia, Spain carlos.simon@ivi.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: Simón
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism*; D000328:Adult; D001284:Atrophy / Q000628:therapy; D001804:Blood Transfusion, Autologous; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D015331:Cohort Studies; D004717:Endometrium / Q000473:pathology; D005260:Female; D006175:Gynatresia / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D014182:Transplantation, Autologous
chemical_list: D000071916:AC133 Antigen; C000606023:PROM1 protein, human
keywords: Asherman's syndrome; CD133+; bone marrow-derived stem cell; cell therapy; endometrial atrophy