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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

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Front. Med.    2022, Vol. 16 Issue (6) : 827-858    https://doi.org/10.1007/s11684-022-0948-8
REVIEW
Cell therapy for the treatment of reproductive diseases and infertility: an overview from the mechanism to the clinic alongside diagnostic methods
Kosar Babaei1, Mohsen Aziminezhad1,2, Seyedeh Elham Norollahi3, Sogand Vahidi4, Ali Akbar Samadani5()
1. Non-Communicable Disease Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
2. UMR INSERM U 1122, IGE-PCV, Interactions Gène-Environment En Physiopathologie Cardiovascular Université De Lorraine, Nancy, France
3. Cancer Research Center and Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
4. Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
5. Guilan Road Trauma Research Center, Guilan University of Medical Sciences, Rasht, Iran
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Abstract

Infertility is experienced by 8%–12% of adults in their reproductive period globally and has become a prevalent concern. Besides routine therapeutic methods, stem cells are rapidly being examined as viable alternative therapies in regenerative medicine and translational investigation. Remarkable progress has been made in understanding the biology and purpose of stem cells. The affected pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) are further studied for their possible use in reproductive medicine, particularly for infertility induced by premature ovarian insufficiency and azoospermia. Accordingly, this study discusses current developments in the use of some kinds of MSCs such as adipose-derived stem cells, bone marrow stromal cells, umbilical cord MSCs, and menstrual blood MSCs. These methods have been used to manage ovarian and uterine disorders, and each technique presents a novel method for the therapy of infertility.
Keywords infertility      stem cell therapy      mesenchymal stem cells      pluripotent stem cells     
Corresponding Author(s): Ali Akbar Samadani   
Just Accepted Date: 12 October 2022   Online First Date: 22 December 2022    Issue Date: 16 January 2023
 Cite this article:   
Kosar Babaei,Mohsen Aziminezhad,Seyedeh Elham Norollahi, et al. Cell therapy for the treatment of reproductive diseases and infertility: an overview from the mechanism to the clinic alongside diagnostic methods[J]. Front. Med., 2022, 16(6): 827-858.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0948-8
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I6/827
Fig.1  Different parameters including nanoparticle carrying MSCs, neural stem cells (NSCs), oncolytic viruses carrying MSCs/NSCs, and genetically altered MSCs/NSCs are associated with the treatment of cancer cells in with corporation chemotherapy.
Identifier Situation Interventions Conditions Trial results Position Reference
NCT02240823 Unknown Adipose-derived stem cells (AdMSCs) Post-radical prostatectomy erectile dysfunction Intracavernous injection of AdMSC is a safe process and resulted in the recovery of the erectile role Odense University Hospital [252]
NCT02603744 Unknown Intraovarian injection of adipose-derived stromal cells (ADSCs) Primary ovarian insufficiency Intraovarian engrafting of ADSCs is safe and possibly related to a decrease in FSH level Royan Institute [253]
NCT02696889 Active Therapeutic potential of autologous stem cell Premature ovarian insufficiency (POI), diminished ovarian reserve A description of two subjects showed considerable progress in clinical characteristics associated with POI. The size and estrogen production increased in the MSC engrafted ovary The University of Illinois at Chicago [254]
NCT00429494 Completed Approach: hematopoietic stem cell transplantation (Hsct)Drug: leuprolide acetate Amenorrhea primary ovarian insufficiency Informed that leuprolide could not maintain an ovarian role in HSCT patients UT MD Anderson Cancer Center, United States [255]
NCT02313415 Completed Approach: Umbilical cord MSCs Infertility with intrauterine adhesions Demonstrated that transplantation of clinical-grade human UC MSC could enhance the proliferative and differentiation efficiency of the endometrium Nanjing Drum Tower Hospital, China [256]
NCT02008799 Recruiting Intra testicular artery injection of bone marrow stem cell Azoospermia None Man Clinic for Andrology, Male Infertility, and Sexual Dysfunction
NCT02204358 Unknown Collagen scaffolds, loaded with human bone marrow-derived stem cells Endometrial dysplasia, intrauterine adhesion (IUA) None Nanjing University Medical School
NCT03207412 Unknown Human amniotic epithelial cells (hAECs) Primary ovarian insufficiency None Chongqing Medical University, China
NCT03592849 Registering by invitation Collagen scaffolds, loaded with human bone marrow-derived MSC Infertile women with thin endometrium None Nanjing Drum Tower Hospital, China
NCT02372474 Completed Biological: stem cell Primary ovarian insufficiency None Al Azhar University, Cairo, Egypt
NCT04009473 Registering by invitation SEGOVA method involves stem cell treatment, PPR therapy, and growth factor None Multicenter
NCT02414295 Completed MSC injection Klinefelter syndrome (KS) None Man Clinic for Andrology and Male Infertility, Cairo, Egypt
NCT04676269 Recruiting Amnion bilayer and stem cell combination treatment Infertile patients with thin endometrium None Indonesia University
NCT01742533 Unknown Biological: human umbilical cord MSCs and human cord blood mononuclear cellsDrug: hormone replacement treatment Primary ovarian insufficiency None Shenzhen People’s Hospital, Shenzhen, Guangdong, China
NCT04706312 Not yet recruiting Human amniotic epithelial cells (hAECs) Diminished ovarian reserve (DOR) None Nanjing Medical University
NCT03166189 Completed Biological: bone marrow–derived MSCs Asherman syndrome None D.O. Ott Research Institute of Obstetrics, Gynecology, Russian Federation
NCT02151890 Completed Biological: stem cell Primary ovarian insufficiency None Al Azhar University, Cairo, Egypt
NCT02041910 Unknown Derived stem cells Azoospermia None Hesham Saeed Elshaer, El-Rayadh Fertility Centre
NCT02641769 Recruiting Intratesticular transplantation of autologous stem cells Non-obstructive azoospermia None Stem Cells of Arabia, Amman, Jordan
NCT03069209 Active Biological: stem cell Primary ovarian insufficiency None Stem Cells Arabia, Amman, Jordan
NCT02713854 Recruiting Human embryonic stem cell-derived trophoblastic spheroids as a predictive instrument Subfertility None The University of Hong Kong
NCT02062931 Unknown Biological: stem cell Primary ovarian insufficiency None Al-Azhar University hospitals, Egypt
NCT02414308 Unknown Adipose tissue stem cells (ASCs) injection Erectile dysfunction (ED) None Man Clinic for Andrology, Male Infertility, and Sexual Dysfunction
NCT02025270 Unknown Azoospermic patients Azoospermic patients Bone marrow-derived MSCs Al Azhar University, Egypt
Tab.1  Clinical trials corresponding stem cell treatment accomplished or underway for modification of infertility
Fig.2  General view of mesenchymal stem cells therapy and introductions of some cellular and molecular elements in this pathway.
Origin Content Role Reference
Human UCMSC-EV miR-21-5p, miR-146a-5p Improved ovarian role in old mice [257]
Human UCMSC-EV miR-147 Repressed M1 [258]
Human ADSC-EV miR-126, miR-146b, miR-199a, miR-223 Generated M2 polarization [259]
Human UCMSC-EV miR-17-5p Enhanced ovarian role, reducing ROS level [260]
Human ADSC-EV miR-323-3p Anti-apoptosis of CCs [192]
Human WJMSC-EV Catalase Reduced ROS level [261]
Human UCMSC-EV TSG-6 Anti-inflammation [262]
Human AMSC-EV miR-320a Reduced ROS level [182]
Human AFMSC-EV miR-146a-5p, miR-548e-5p Anti-inflammation [263]
Human UCMSC-EV Let7b Phenotypic transformation of M1 to M2 inhibited pro-fibrotic genes (TGF-b1/TGFbR1, collagen IVa1) [264,265]
Human BMSC-EV EGF, FGF, PDGF, NF?B signaling proteins Generated angiogenesis [266]
Human BMSC-EV STAT3, Wnt3a Migration, elevated angiogenesis and fibroblast proliferation [266]
Human BMSC-EV MFG-E8 Attenuated renal fibrosis partly by interfering with the RhoA/ROCK pathway [257]
Human ADSC-EV SCF, MFG-E8, c-kit, ANGPTL1, thrombopoietin Promoted angiogenesis [267]
Human BMSC-EV miR-216a-5p Promoted M2 polarization [257]
Human BMSC-EV IL-10 Anti-inflammation [268]
Human dental pulp MSC-EVs Jagged1 Induced angiogenesis [269 ]
Human ADSC-EV miR-30b, miR-125a Elevated angiogenesis through suppressing DLL4-Notch signaling pathway [270]
Human UCMSC-EV Wnt4 Improved angiogenesis by elevating Wnt4/b-catenin signaling [271]
Human BMSC-EV KGF Reduced inflammation and caused M2 polarization [272]
Human ADSC-EVMice BMSC-EV VEGF Improved neovascularization through elevating VEGF/VEGFR signaling pathway [268]
Rat BMSC-EV miR-130a Advanced angiogenesis [276]
Rat BMSC-EV miR-340 Attenuation endometrial fibrosis [273]
Rat AFMSC-EV miR-21 Enhanced ovarian role [179]
Rat BMSC-EV miR-144-5p [257]
Mice AFMSC-EV miR-10a Enhanced ovarian role and anti-apoptosis of GCs [176]
Mice BMSC-EV miR-210 Enhanced angiogenesis, limited fibrosis in ischemic hearts [270]
Mice BMSC-EV HGF Stabilized endothelial barrier role [270]
Mice BMSC-EV miR-644-5p Anti-apoptosis of GCs [274]
MSC-EVMice BMSC-EV miR-210 Elevating angiogenesis via VEGF pathway, ameliorating inflammation through miR-210/serpine1 axis [270]
Mouse BMSC-EV miR-182 Generated M2 polarization through targeting TLR4 [275]
Pig ADSC-EV Angptl4, Ephrin-B2, PDGFC, DOK2, Wnt7b Elevated angiogenesis [276]
Pig ADSC-EV ACVR1, MMP19 Matrix remodeling [276]
CMPC-MSC-Exo EMMPRIN Elevated angiogenesis [277]
EndMSC-EV Dog WJMSC-EV TGF-b Matrix remodeling, prevented CD4+ T cells activation [278]
MSC-EV CXCL2, CXCL8, DEFA1, HERC5, IFITM2,CXCL16 Recruited immune cells to proximity of MSC-EVs [279]
MSC-EV miR-21, miR-132, miR-222, IL-8 Elevated angiogenesis [280]
MSC-EV miR-29 Attenuation renal fibrosis and EMT through targeting PI3K/AKT signaling pathway [281]
MSC-EV miR-145 Attenuated EMT by suppressing TGF-b/smad signaling or repressing ZEB2 [281]
Tab.2  Different microRNAs and genes alongside their stem cell origination and their performance
Fig.3  In this picture, the involvement of peripheral blood mononuclear cells and human amniotic epithelial cells are shown with another cellular.
MSC kinds Model Cause Therapy Results Reference
MB-MSCs Endometrial disorders Human Severe aortic stenosis (AS) Provide via the cervix to the fundus of the uterus ↑ Endometrial thickness (EMT) [282]
Rat Intrauterine adhesion (IUA) is caused by mechanical injury Local injection ↑ Pregnancy rate [79]
Ovarian failure Mice Cisplatin-induced POF Local injection ↑ Fibroblast growth factor 2↑ Ovarian role [283]
Mice CTX-induced POF Local injection ↓Hormone secretion↑Ovarian weight [102]
Bone marrow stromal cells Endometrial disorders Human Refractory aortic stenosis (AS) Uterine artery injection Rebuild the endometrium [113]
Mice 24-gauge needle-caused Marked with SPIOs local/tail vein injection ↑Endometrial proliferation [284]
Ovarian failure Mice CTX-induced ovarian disorders Local injection Repair ovarian hormone exposition [285]
Rabbit CTX-induced ovarian disorders Intravenous injection ↑Ovarian role [286]
UC-MSCs Endometrial disorders Human Uterine niche Local intramuscular injection ↑ Uterine scar rebuilds↓Uterine niche occurrence [287]
Rat 95% ethanol-induced endometrial injury Tail vein injection ↓ Endometrial fibrosis↑ Fertility and angiogenesis [84]
Endometrial disorders Rat Perimenopausal ovary Tail vein injection ↓ Follicle-exciting hormone↑ Estradiol and follicle number [288]
Rat Paclitaxel-induced POF Local injection ↓ Follicle-exciting hormone↑ Estradiol and ovarian role [81]
Mice Busulfan CTX-induced primary ovarian failure Local injection ↑ Ovarian role and fertility [79]
Mice CTX-induced POF Tail vein injection ↑Estradiol, weight of the ovaries [289]
Adipose-derived stem cells Endometrial disorders Rat Trichloroacetic acid-induced aortic stenosis (AS) Intraperitoneal injection ↑Endometrial proliferation↓Fibrosis [290]
Ovarian failure Rat TG-induced ovarian injury Collagen scaffold ↑Fertility [291]
Mice Cisplatin-cause ovarian disorder Local injection ↑Ovarian role [292]
Tab.3  MSC therapy is being used to improve female reproductive problems
Fig.4  Associations of extracellular vesicles and mesenchymal transfer in contraction with MSCs.
Nature of cells Immuno-rejection Self-renewal capacity Source of generation Clinical applications Ethical concerns
Mesenchymal stem cells Multipotent No Mesodermal-derived tissue, like adipose tissue, muscle, cartilage, bone Human somatic cells Widely utilized No ethical or moral concerns
Embryonic stem cells Pluripotent Yes Differentiate into results of main germ layers Inner cell mass cells of blastocysts Limited Ethical and moral concerns present
Spermatogonial stem cells Pluripotent Yes Differentiate into the results of all primary germ layers Testicular tissues Widely utilized No ethical or moral concerns
Induced pluripotent stem cells Pluripotent Yes Differentiate into the results of all primary germ layers Adipose tissue, bone marrow, cord blood Widely utilized No ethical or moral concerns
Tab.4  Stem cell features in infertility therapy
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