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Improvement of Pregnancy Rate and Live Birth Rate in Poor Ovarian Responders by Intraovarian Administration of Autologous Menstrual Blood Derived- Mesenchymal Stromal Cells: Phase I/II Clinical Trial

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Abstract

The study was aimed to evaluate the safety and efficacy of cell therapy using autologous menstrual blood derived- mesenchymal stromal cells (Men-MSCs) in fertility potential of poor ovarian responders (PORs). POR women were divided into mesenchymal stroma cell (MSC) therapy (n = 15) and routine ICSI (n = 16) groups. The cultured Men-MSCs were autologously injected into left ovary of MSC group after approval by flow cytometry, karyotyping, endotoxin, sterility and mycoplasma tests. Changes in anti-Mullerian hormone (AMH), antral follicles count (AFC), oocytes and embryos number, clinical pregnancy rate and live birth rate were followed in both groups up to one year after treatment. 4 of 15 participants in MSC group got naturally pregnant during 3 months after cell administration, in contrast to no natural conception in control group (P = 0.04). The mean AMH level did not significantly differ with that of previous cycle or control group. Although mean AFC and oocytes number in MSC group did not indicate considerable difference with those of control group, raise of these parameters in comparison with previous cycle was significant (both P = 0.01). Nonetheless, oocyte fertilization rate and embryo number in MSC group were higher than control group (P = 0.04 and P = 0.008, respectively). Altogether, 7 of 15 women in MSC group and 2 of 16 women in routine ICSI group had clinical pregnancy that resulted in 5 live births in main group and one birth in control group. In conclusion, cell therapy using Men-MSCs could be considered as a potential treatment to restore fertility capability of POR women.

The trial registration number (TRN): IRCT20180619040147N2.

Date of registration: 2018-08-21.

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Acknowledgments

The authors would like to appreciate Dr.Mohammad-Reza Sadeghi (Chairman of Avicenna Research Institute), Dr. Ali Sadeghi-Tabar (Managing director of Avicenna Infertility Clinic), Miss. Haleh Edalatkhah (Quality Control Assistant), Mrs. Somayeh Khorasani (production line assistant), Mrs. Zohreh Fathi (supervisor of embryology lab) and Mrs. Fariba Mohammadi (supervisor of operation room) for their assistance in implementation of this project.

Funding

This study was financially supported by Avicenna Research Institute (grant number: 960110–029).

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Authors and Affiliations

  1. Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, P.O. Box 19615-1177, Islamic Republic of Iran

    Simin Zafardoust, Somaieh Kazemnejad, Maryam Darzi, Mina Fathi-Kazerooni, Hilda Rastegari & Afsaneh Mohammadzadeh

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  1. Simin Zafardoust
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Contributions

Simin Zafardoust: As a gynaecologist, part of study design, selection and randomization of patients, stem cell injection into ovaries and follow up of participants were performed by her.

Somaieh Kazemnejad: Study design, supervision of entire cell production, quality control and administration along with manuscript writing and editing were performed by her.

Maryam Darzi: She had contribution in stem cell isolation, culture and characterization.

Mina Fathi-Kazerooni: Quality Assurance manager.

Hilda Rastegari: Quality control of culture stem cells was implemented by her.

Afsaneh Mohammadzadeh: She had contribution in participant’s selection and their follow up after stem cell administration.

Corresponding author

Correspondence to Somaieh Kazemnejad.

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Competing Interests

The authors declare that they have no competing interests.

Ethics Approval

The study was started after providing complete information to patients and obtaining signed written consent. All the procedures in this clinical trial study were conducted according to the Declaration of Helsinki, Good Clinical Practice or good manufacturing practice (GMP) guideline approved by Biomedical Research Ethics Committee of Academic Center for Education, Culture and Research (ACECR, Tehran, Iran). The study was registered at the Iranian Registry of Clinical Trials (IRCT20180619040147N2). The cell manufacturing was performed by STERCO (Tehran, Iran) in GMP clean room authorized by Iran food and drug administration authorities.

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Simin Zafardoust and Somaieh Kazemnejad are equally the first author

Electronic supplementary material

Supplementary Fig. 1

Flow chart of isolation, culture, expansion, banking, and infusion of Men-MSCs (JPG 1.42 mb)

Supplementary Fig. 2

Morphology of menstrual blood stem cells in the first passage obtained from each participant in the cell therapy group. Scale bar: 300 μM (JPG 4.74 mb)

Supplementary Fig. 3

Immunophenotypic properties of cultured cells were assessed by flow cytometry. In brief, aliquots of 105 cells/100 μL were incubated separately with PE-conjugated anti-human CD73 (clone AD2; BD Pharmingen) or PE-conjugated anti human CD44 (clone 515;BD Pharmingen), CD90 (clone 5E10; BioLegend), CD45 (clone 2D1; BioLegend) for 30 min at 4 °C. Afterwards, all cell suspensions were washed twice with PBS-fetal bovine serum 2% and analyzed using a flow cytometer (Partec GmbH, Munster, Germany) using appropriate isotype controls. Representative histograms for CD markers of two samples (first participant and 15th participant) are demonstrated (gray). The respective isotype control is shown as black line. (JPG 614 kb)

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Zafardoust, S., Kazemnejad, S., Darzi, M. et al. Improvement of Pregnancy Rate and Live Birth Rate in Poor Ovarian Responders by Intraovarian Administration of Autologous Menstrual Blood Derived- Mesenchymal Stromal Cells: Phase I/II Clinical Trial. Stem Cell Rev and Rep 16, 755–763 (2020). https://doi.org/10.1007/s12015-020-09969-6

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