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Cevik EC, Mamillapalli R, Taylor HS. Stem cells and female reproduction: endometrial physiology, disease and therapy. Stem Cells 2025; 43:sxaf016. [PMID: 40317260 DOI: 10.1093/stmcls/sxaf016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 12/11/2024] [Indexed: 05/07/2025]
Abstract
The human endometrium, a dynamic tissue that undergoes cyclical shedding, repair, regeneration, and remodeling, relies on progenitor stem cells for replenishment. Bone marrow-derived mesenchymal stem cells (BM-MSCs) also may play a crucial role in the physiological process of endometrial regeneration, augmenting endometrial repair, supporting pregnancy, and thereby making a major contribution to reproduction. Notably, defective or inappropriate recruitment and engraftment of stem cells are implicated in various reproductive diseases, including endometriosis, highlighting the potential therapeutic avenues offered by stem cell-targeted interventions. Endometrial progenitor cells have shown promise in improving pregnancy outcomes and addressing infertility issues. Furthermore, BM-MSCs demonstrate the potential to reverse pathologies, including Asherman's syndrome and thin endometrium, offering novel approaches to treating infertility, implantation failure, and recurrent pregnancy loss. Mobilization of endogenous stem cells to areas of pathology through chemoattractants also presents a promising strategy for targeted therapy. Finally, endometrium-derived mesenchymal stem cells, characterized by their multipotent nature and ease of collection through minimally invasive techniques, hold promise in a wide range of reproductive and non-reproductive pathologies, including diabetes, kidney disease, Parkinson's disease, or cardiac disorders. As the best of our knowledge of stem cell biology continues to grow, the incorporation of stem cell-based therapies into clinical practice presents significant potential to transform reproductive medicine and enhance patient outcomes.
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Affiliation(s)
- E Cansu Cevik
- Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06520, United States
| | - Ramanaiah Mamillapalli
- Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06520, United States
| | - Hugh S Taylor
- Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06520, United States
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Sadiasa A, Werkmeister JA, Gurung S, Gargett CE. Steps towards the clinical application of endometrial and menstrual fluid mesenchymal stem cells for the treatment of gynecological disorders. Expert Opin Biol Ther 2025; 25:285-307. [PMID: 39925343 DOI: 10.1080/14712598.2025.2465826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 01/28/2025] [Accepted: 02/07/2025] [Indexed: 02/11/2025]
Abstract
INTRODUCTION The human endometrium is a highly regenerative tissue that contains mesenchymal stem/stromal cells (MSCs). These MSCs are sourced via office-based biopsies and menstrual fluid, providing a less invasive and readily available option for cell-based therapies. This review provides an update on endometrial-derived MSCs as a treatment option for gynecological diseases. AREAS COVERED This narrative review covers the characterization and therapeutic mechanisms of endometrium biopsy-derived MSCs (eMSCs) and menstrual fluid-derived mesenchymal stromal cells (MenSCs), highlighting similarities and differences. It also covers studies of their application in preclinical animal models and in clinical trials as potential cell-based therapies for gynecological diseases. EXPERT OPINION eMSCs and MenSCs from a homologous tissue source have the potential to promote regenerative activity as a treatment for gynecological diseases. Both eMSCs and MenSCs demonstrate therapeutic benefits through their paracrine activity in tissue regeneration, immunomodulation, angiogenesis, and mitigating fibrosis. Further research is essential to establish standardized isolation and characterization protocols, particularly for heterogeneous MenSCs, and to fully understand their mechanisms of action. Implementing SUSD2 magnetic bead sorting for purifying eMSCs from endometrial tissues and menstrual fluid is crucial for their use in future cell-based therapies. Optimization of production, storage, and delivery methods will maximize their therapeutic effectiveness.
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Affiliation(s)
- Alexander Sadiasa
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Jerome A Werkmeister
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Shanti Gurung
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Caroline E Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
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Dai F, Wang R, Deng Z, Yang D, Wang L, Wu M, Hu W, Cheng Y. Comparison of the different animal modeling and therapy methods of premature ovarian failure in animal model. Stem Cell Res Ther 2023; 14:135. [PMID: 37202808 DOI: 10.1186/s13287-023-03333-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 04/06/2023] [Indexed: 05/20/2023] Open
Abstract
Incidence of premature ovarian failure (POF) is higher with the increase of the pace of life. The etiology of POF is very complex, which is closely related to genes, immune diseases, drugs, surgery, and psychological factors. Ideal animal models and evaluation indexes are essential for drug development and mechanism research. In our review, we firstly summarize the modeling methods of different POF animal models and compare their advantages and disadvantages. Recently, stem cells are widely studied for tumor treatment and tissue repair with low immunogenicity, high homing ability, high ability to divide and self-renew. Hence, we secondly reviewed recently published data on transplantation of stem cells in the POF animal model and analyzed the possible mechanism of their function. With the further insights of immunological and gene therapy, the combination of stem cells with other therapies should be actively explored to promote the treatment of POF in the future. Our article may provide guidance and insight for POF animal model selection and new drug development.
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Affiliation(s)
- Fangfang Dai
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Ruiqi Wang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Zhimin Deng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Dongyong Yang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Linlin Wang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Mali Wu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Wei Hu
- Department of Obstetrics and Gynecology Ultrasound, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Yanxiang Cheng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
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Zafardoust S, Kazemnejad S, Darzi M, Fathi-Kazerooni M, Saffarian Z, Khalili N, Edalatkhah H, Mirzadegan E, Khorasani S. Intraovarian Administration of Autologous Menstrual Blood Derived-Mesenchymal Stromal Cells in Women with Premature Ovarian Failure. Arch Med Res 2023; 54:135-144. [PMID: 36702667 DOI: 10.1016/j.arcmed.2022.12.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 11/12/2022] [Accepted: 12/20/2022] [Indexed: 01/26/2023]
Abstract
BACKGROUND Premature ovarian failure (POF) is a well-known cause of infertility, particularly in women under the age of 40. POF is also associated with elevated gonadotropin levels, amenorrhea and sex-hormone deficiency. AIM OF THE STUDY In this study, the therapeutic potential of autologous mesenchymal stromal cells obtained from menstrual blood (Men-MSCs) for patients with POF was evaluated. METHODS 15 POF patients were included in the study. The cultured Men-MSCs were confirmed by flow cytometry, karyotype, endotoxin and mycoplasma and were then injected into the patients' right ovary by vaginal ultrasound guidance and under general anesthesia and aseptic conditions. Changes in patients' anti-Müllerian hormone (AMH), antral follicle count (AFC), follicle-stimulating hormone (FSH), luteal hormone (LH), and estradiol (E2) levels, as well as general flushing and vaginal dryness were followed up to one year after treatment. RESULTS All patients were satisfied with a decrease in general flushing and vaginal dryness. 4 patients (2.9%) showed a spontaneous return of menstruation without additional pharmacological treatment. There was a significant difference in AFC (0 vs. 1 ± 0.92 count, p value ≤0.001%), FSH (74 ± 22.9 vs. 54.8 ± 17.5 mIU/mL, p-value ≤0.05%), E2 (10.2 ± 6 vs. 21.8 ± 11.5 pg/mL p-value ≤0.01%), LH (74 ± 22.9 vs. 54.8 ± 17.5 IU/L,p-value ≤0.01%) during 3 months post-injection. However, there were no significant changes in AMH (p-value ≥0.05%). There were also no significant differences in assessed parameters between 3 and 6 months after cell injection. CONCLUSION According to the findings of this study, administration of Men-MSCs improved ovarian function and menstrual restoration in some POF patients.
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Affiliation(s)
- Simin Zafardoust
- Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Somaieh Kazemnejad
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
| | - Maryam Darzi
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Mina Fathi-Kazerooni
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Zahra Saffarian
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Niloofar Khalili
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Haleh Edalatkhah
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Ebrahim Mirzadegan
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Somayeh Khorasani
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
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Babaei K, Aziminezhad M, Norollahi SE, Vahidi S, Samadani AA. Cell therapy for the treatment of reproductive diseases and infertility: an overview from the mechanism to the clinic alongside diagnostic methods. Front Med 2022; 16:827-858. [PMID: 36562947 DOI: 10.1007/s11684-022-0948-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 06/28/2022] [Indexed: 12/24/2022]
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.
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Affiliation(s)
- Kosar Babaei
- Non-Communicable Disease Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Mohsen Aziminezhad
- Non-Communicable Disease Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.,UMR INSERM U 1122, IGE-PCV, Interactions Gène-Environment En Physiopathologie Cardiovascular Université De Lorraine, Nancy, France
| | - Seyedeh Elham Norollahi
- Cancer Research Center and Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Sogand Vahidi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Guilan University of Medical Sciences, Rasht, Iran.
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Ludke A, Hatta K, Yao A, Li RK. Uterus: A Unique Stem Cell Reservoir Able to Support Cardiac Repair via Crosstalk among Uterus, Heart, and Bone Marrow. Cells 2022; 11:cells11142182. [PMID: 35883625 PMCID: PMC9324611 DOI: 10.3390/cells11142182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/09/2022] [Accepted: 07/12/2022] [Indexed: 11/16/2022] Open
Abstract
Clinical evidence suggests that the prevalence of cardiac disease is lower in premenopausal women compared to postmenopausal women and men. Although multiple factors contribute to this difference, uterine stem cells may be a major factor, as a high abundance of these cells are present in the uterus. Uterine-derived stem cells have been reported in several studies as being able to contribute to cardiac neovascularization after injury. However, our studies uniquely show the presence of an “utero-cardiac axis”, in which uterine stem cells are able to home to cardiac tissue to promote tissue repair. Additionally, we raise the possibility of a triangular relationship among the bone marrow, uterus, and heart. In this review, we discuss the exchange of stem cells across different organs, focusing on the relationship that exists between the heart, uterus, and bone marrow. We present increasing evidence for the existence of an utero-cardiac axis, in which the uterus serves as a reservoir for cardiac reparative stem cells, similar to the bone marrow. These cells, in turn, are able to migrate to the heart in response to injury to promote healing.
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Affiliation(s)
- Ana Ludke
- Division of Cardiovascular Surgery, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; (A.L.); (K.H.); (A.Y.)
| | - Kota Hatta
- Division of Cardiovascular Surgery, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; (A.L.); (K.H.); (A.Y.)
| | - Alina Yao
- Division of Cardiovascular Surgery, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; (A.L.); (K.H.); (A.Y.)
| | - Ren-Ke Li
- Division of Cardiovascular Surgery, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; (A.L.); (K.H.); (A.Y.)
- Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada
- Correspondence: ; Tel.: +1-416-581-7492
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Dubey A, Saini S, Sharma V, Malik H, Kumar D, De AK, Bhattacharya D, Malakar D. Deducing Insulin-Producing Cells from Goat Adipose Tissue-Derived Mesenchymal Stem Cells. Cell Reprogram 2022; 24:195-203. [PMID: 35787695 DOI: 10.1089/cell.2022.0029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Mesenchymal stem cell is a potent tool for regenerative medicine against control of incurable diseases in human and animals. Diabetes mellitus is one such condition marked with the blood glucose is high due to lack of insulin (INS) hormone secreted by the pancreatic cells. Rare, but sporadic, cases of dysfunctional pancreatic cells in goat as well as the promises of stem cell therapy as an off-the-shelf medicine prompted us to explore the potential of adipose-derived goat mesenchymal stem cells (AD-MSCs) to transdifferentiate into pancreatic islet-like cells. We isolated, in vitro cultured, and characterized the AD-MSCs by expression of MSC-specific markers and differentiation into multiple mesodermal lineage cells. The characterized AD-MSCs were in vitro transdifferentiated into INS-producing islet-like cells using a cocktail of glucose, nicotinamide, activin-A, exendin-4, pentagastrin, retinoic acid, and mercaptoethanol in 3 weeks. The transdifferentiated islet-like cells demonstrated the expression of pancreatic endoderm-specific transcripts PDX1, NGN3, PAX6, PAX4, ISL1, and GLUT2 as well as protein expression of pancreatic and duodenal homeobox 1 (PDX1), INS, and Islets 1 (ISL1). The islet-like cells also demonstrated the significant glucose-dependent INS release with respect to the course of transdifferentiation regime. The study envisaged to create the building material for basic research into mechanism of glucose homeostasis, which may pave road for developments in diabetes drug discovery and regenerative therapies.
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Affiliation(s)
- Amit Dubey
- Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, India
| | - Sikander Saini
- Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, India
| | - Vishal Sharma
- Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, India
| | - Hrudananda Malik
- Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, India
| | - Dinesh Kumar
- Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, India
| | - Arun Kumar De
- Animal Science Division, ICAR-Central Island Agricultural Research Institute, Port Blair, India
| | - Debasis Bhattacharya
- Animal Science Division, ICAR-Central Island Agricultural Research Institute, Port Blair, India
| | - Dhruba Malakar
- Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, India
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Mamillapalli R, Cho S, Mutlu L, Taylor HS. Therapeutic role of uterine-derived stem cells in acute kidney injury. Stem Cell Res Ther 2022; 13:107. [PMID: 35279204 PMCID: PMC8917641 DOI: 10.1186/s13287-022-02789-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 02/27/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Acute kidney injury (AKI) causes abrupt deterioration in kidney function that disrupts metabolic, electrolyte and fluid homeostasis. Although the prevalence of AKI is steadily increasing, no definitive treatment options are available, leading to severe morbidity and mortality. We evaluated the role of uterine-derived multipotent stem cells in kidney regeneration after ischemic AKI. METHODS Female C57BL/6J mice were hysterectomized and subsequently subject to AKI by either unilateral or bilateral renal ischemia-reperfusion injury. Uterine-derived cells (UDCs), containing a population of uterine stem cells, were isolated from the uteri of female transgenic DsRed mice and injected intravenously to AKI mice. Engraftment of DsRed cells was analyzed by flow cytometry while serum creatinine levels were determined colorimetrically. Expression of UDC markers and cytokine markers were analyzed by immunohistochemical and qRT-PCR methods, respectively. The Kaplan-Meier method was used to analyze survival time while unpaired t test with Welch's correction used for data analysis between two groups. RESULTS Mice with an intact uterus, and hence an endogenous source of UDCs, had a higher survival rate after bilateral ischemic AKI compared to hysterectomized mice. Mice treated with infusion of exogenous UDCs after hysterectomy/AKI had lower serum creatinine levels and higher survival rates compared to controls that did not receive UDCs. Engraftment of labeled UDCs was significantly higher in kidneys of bilateral ischemic AKI mice compared to those that underwent a sham surgery. When unilateral ischemic AKI was induced, higher numbers of UDCs were found in the injured than non-injured kidney. Immunofluorescence staining demonstrated double-positive DsRed/Lotus tetragonolobus agglutinin (LTA) positive cells and DsRed/CD31 positive cells indicating contribution of UDCs in renal tubular and vascular regeneration. Expression of Cxcl12, Bmp2, Bmp4, and Ctnf in renal tissue was significantly higher in the UDCs injection group than the control group. CONCLUSIONS UDCs engrafted injured kidneys, contributed to proximal tubule and vascular regeneration, improved kidney function and increased survival in AKI mice. UDC administration is a promising new therapy for AKI. Endogenous uterine stem cells likely also preserve kidney function, suggesting a novel interaction between the uterus and kidney. We suggest that hysterectomy may have a detrimental effect on response to renal injury.
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Affiliation(s)
- Ramanaiah Mamillapalli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 310 Cedar Street, New Haven, CT, 06510, USA.
| | - SiHyun Cho
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 310 Cedar Street, New Haven, CT, 06510, USA
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, College of Medicine, Yonsei University, Seoul, South Korea
| | - Levent Mutlu
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 310 Cedar Street, New Haven, CT, 06510, USA
| | - Hugh S Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 310 Cedar Street, New Haven, CT, 06510, USA
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Chen JM, Huang QY, Zhao YX, Chen WH, Lin S, Shi QY. The Latest Developments in Immunomodulation of Mesenchymal Stem Cells in the Treatment of Intrauterine Adhesions, Both Allogeneic and Autologous. Front Immunol 2021; 12:785717. [PMID: 34868069 PMCID: PMC8634714 DOI: 10.3389/fimmu.2021.785717] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022] Open
Abstract
Intrauterine adhesion (IUA) is an endometrial fibrosis disease caused by repeated operations of the uterus and is a common cause of female infertility. In recent years, treatment using mesenchymal stem cells (MSCs) has been proposed by many researchers and is now widely used in clinics because of the low immunogenicity of MSCs. It is believed that allogeneic MSCs can be used to treat IUA because MSCs express only low levels of MHC class I molecules and no MHC class II or co-stimulatory molecules. However, many scholars still believe that the use of allogeneic MSCs to treat IUA may lead to immune rejection. Compared with allogeneic MSCs, autologous MSCs are safer, more ethical, and can better adapt to the body. Here, we review recently published articles on the immunomodulation of allogeneic and autologous MSCs in IUA therapy, with the aim of proving that the use of autologous MSCs can reduce the possibility of immune rejection in the treatment of IUAs.
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Affiliation(s)
- Jia-Ming Chen
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Qiao-Yi Huang
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yun-Xia Zhao
- Department of Gynaecology and Obstetrics, Shenzhen Hospital of University of Hong Kong, Shenzhen, China
| | - Wei-Hong Chen
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.,Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Qi-Yang Shi
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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Mo Y, Wang Z, Gao J, Yan Y, Ren H, Zhang F, Qi N, Chen Y. Comparative study of three types of mesenchymal stem cell to differentiate into pancreatic β-like cells in vitro. Exp Ther Med 2021; 22:936. [PMID: 34335885 PMCID: PMC8290435 DOI: 10.3892/etm.2021.10368] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 05/11/2021] [Indexed: 12/18/2022] Open
Abstract
Type 1 diabetes (TID) is a chronic metabolic disease where the body produces insufficient or no insulin. Stem cells with multi-directional differentiation potential are transplanted and differentiate into β-like cells in vivo to replace pancreatic β cells, which has become a novel treatment strategy. The aim of the present study was to investigate the ability of three types of adult mesenchymal stem cell (MSC) to differentiate into pancreatic β-like cells in vitro in order to identify suitable sources for the treatment of diabetes. The three MSC types were menstrual blood-derived MSCs (MENSCs), umbilical cord-derived MSCs (UCMSCs) and dental pulp MSCs (DPSCs). The differentiation method used in the present study was divided into three steps and the MSCs were differentiated into pancreatic β-like cells in vitro. Among these MSCs, MENSCs had a greater ability to differentiate into islet β-like cells in vitro, while UCMSCs and DPSCs exhibited a similar differentiation potency, which was relatively lower compared with that of MENSCs. The present results indicated that MENSCs may be a suitable cell source for the curative treatment of TID.
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Affiliation(s)
- Yunfang Mo
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
| | - Zejian Wang
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
| | - Jian Gao
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
| | - Yan Yan
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
| | - Huaijuan Ren
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
| | - Fengli Zhang
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
| | - Nianmin Qi
- China Stem Cell Therapy Co., Ltd., Shanghai 201203, P.R. China
| | - Yantian Chen
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
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11
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Saha S, Roy P, Corbitt C, Kakar SS. Application of Stem Cell Therapy for Infertility. Cells 2021; 10:1613. [PMID: 34203240 PMCID: PMC8303590 DOI: 10.3390/cells10071613] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 02/06/2023] Open
Abstract
Infertility creates an immense impact on the psychosocial wellbeing of affected couples, leading to poor quality of life. Infertility is now considered to be a global health issue affecting approximately 15% of couples worldwide. It may arise from factors related to the male (30%), including varicocele, undescended testes, testicular cancer, and azoospermia; the female (30%), including premature ovarian failure and uterine disorders; or both partners (30%). With the recent advancement in assisted reproduction technology (ART), many affected couples (80%) could find a solution. However, a substantial number of couples cannot conceive even after ART. Stem cells are now increasingly being investigated as promising alternative therapeutics in translational research of regenerative medicine. Tremendous headway has been made to understand the biology and function of stem cells. Considering the minimum ethical concern and easily available abundant resources, extensive research is being conducted on induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSC) for their potential application in reproductive medicine, especially in cases of infertility resulting from azoospermia and premature ovarian insufficiency. However, most of these investigations have been carried out in animal models. Evolutionary divergence observed in pluripotency among animals and humans requires caution when extrapolating the data obtained from murine models to safely apply them to clinical applications in humans. Hence, more clinical trials based on larger populations need to be carried out to investigate the relevance of stem cell therapy, including its safety and efficacy, in translational infertility medicine.
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Affiliation(s)
- Sarama Saha
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh 249203, India;
| | - Partha Roy
- Department of Biotechnology, Indian Institute of Technology, Roorkee 247667, India;
| | - Cynthia Corbitt
- Department of Biology, University of Louisville, Louisville, KY 40292, USA;
| | - Sham S. Kakar
- Department of Physiology and James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40292, USA
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Lv Q, Wang L, Luo X, Chen X. Adult stem cells in endometrial regeneration: Molecular insights and clinical applications. Mol Reprod Dev 2021; 88:379-394. [PMID: 34014590 PMCID: PMC8362170 DOI: 10.1002/mrd.23476] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 03/23/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023]
Abstract
Endometrial damage is an important cause of female reproductive problems, manifested as menstrual abnormalities, infertility, recurrent pregnancy loss, and other complications. These conditions are collectively termed "Asherman syndrome" (AS) and are typically associated with recurrent induced pregnancy terminations, repeated diagnostic curettage and intrauterine infections. Cancer treatment also has unexpected detrimental side effects on endometrial function in survivors independently of ovarian effects. Endometrial stem cells act in the regeneration of the endometrium and in repair through direct differentiation or paracrine effects. Nonendometrial adult stem cells, such as bone marrow-derived mesenchymal stem cells and umbilical cord-derived mesenchymal stem cells, with autologous and allogenic applications, can also repair injured endometrial tissue in animal models of AS and in human studies. However, there remains a lack of research on the repair of the damaged endometrium after the reversal of tumors, especially endometrial cancers. Here, we review the biological mechanisms of endometrial regeneration, and research progress and challenges for adult stem cell therapy for damaged endometrium, and discuss the potential applications of their use for endometrial repair after cancer remission, especially in endometrial cancers. Successful application of such cells will improve reproductive parameters in patients with AS or cancer. Significance: The endometrium is the fertile ground for embryos, but damage to the endometrium will greatly impair female fertility. Adult stem cells combined with tissue engineering scaffold materials or not have made great progress in repairing the injured endometrium due to benign lesions. However, due to the lack of research on the repair of the damaged endometrium caused by malignant tumors or tumor therapies, the safety and effectiveness of such stem cell-based therapies need to be further explored. This review focuses on the molecular insights and clinical application potential of adult stem cells in endometrial regeneration and discusses the possible challenges or difficulties that need to be overcome in stem cell-based therapies for tumor survivors. The development of adult stem cell-related new programs will help repair damaged endometrium safely and effectively and meet fertility needs in tumor survivors.
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Affiliation(s)
- Qiaoying Lv
- Department of GynecologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
| | - Lulu Wang
- Department of GynecologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
| | - Xuezhen Luo
- Department of GynecologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
| | - Xiaojun Chen
- Department of GynecologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
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Sheikholeslami A, Kalhor N, Sheykhhasan M, Jannatifar R, Sahraei SS. Evaluating differentiation potential of the human menstrual blood-derived stem cells from infertile women into oocyte-like cells. Reprod Biol 2021; 21:100477. [PMID: 33401233 DOI: 10.1016/j.repbio.2020.100477] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 11/09/2020] [Accepted: 12/15/2020] [Indexed: 02/08/2023]
Abstract
One of the most intricate infertility problems among women is the number and quality of the oocytes. Menstrual blood-derived stem cells (MenSCs) are a recently discovered source of mesenchymal stem cells which is known as a suitable source of cells for regenerative medicine. We aimed to investigate whether MenSCs as autologous cell source from endometriosis, PCOS, and healthy women have different characteristics regarding their morphology, CD marker expression pattern, differentiation potential into oocyte-like cells, and oocyte-related genes expression. Menstrual blood samples (1-2 ml) from healthy and infertile women (PCOS and endometriosis) in the age range of 22-35 years were collected. Isolated MenSCs by the Ficoll-Paque density-gradient centrifugation method was characterized by flow cytometry. MenSCs were induced under 20 % follicular fluid (FF), and then they were evaluated for differentiation by Real time-PCR and immunocytochemistry assay. MenSCs derived from endometriosis women had different morphology from PCOS and healthy women, but similar regarding their CD marker pattern. All induced MenSCs showed morphological changes and expressed oocyte related genes (STELLA, GDF9, STRA8, PRDM, LHR, FSHR, SCP3, DDX4, and ZP2) in the 2nd week of culture, but there was a significant difference between the groups. Endometriosis-derived MenSCs showed higher levels of both gene and protein expressions. These findings propose that MenSCs derived from endometriosis and PCOS patients under 20 % FF, not only could differentiate into oocyte-like cells, but also showed more differential potential in comparison with healthy women. This indicates the possibility of using the patients' own MenSCs to differentiate into the oocyte-like cells.
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Affiliation(s)
- Azar Sheikholeslami
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research, Qom Branch, Qom, Iran
| | - Naser Kalhor
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research, Qom Branch, Qom, Iran
| | - Mohsen Sheykhhasan
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research, Qom Branch, Qom, Iran
| | - Rahil Jannatifar
- Department of Reproductive Biology, Academic Center for Education, Culture and Research, Qom Branch, Qom, Iran
| | - Seyedeh Saeideh Sahraei
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research, Qom Branch, Qom, Iran; Department of Reproductive Biology, Academic Center for Education, Culture and Research, Qom Branch, Qom, Iran.
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14
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Kh S, Haider KH. Stem Cells: A Renewable Source of Pancreatic β-Cells and Future for Diabetes Treatment. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Ghoneim MA, Refaie AF, Elbassiouny BL, Gabr MM, Zakaria MM. From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Progress and Challenges. Stem Cell Rev Rep 2020; 16:1156-1172. [PMID: 32880857 PMCID: PMC7667138 DOI: 10.1007/s12015-020-10036-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal cells (MSCs) are an attractive option for cell therapy for type 1 diabetes mellitus (DM). These cells can be obtained from many sources, but bone marrow and adipose tissue are the most studied. MSCs have distinct advantages since they are nonteratogenic, nonimmunogenic and have immunomodulatory functions. Insulin-producing cells (IPCs) can be generated from MSCs by gene transfection, gene editing or directed differentiation. For directed differentiation, MSCs are usually cultured in a glucose-rich medium with various growth and activation factors. The resulting IPCs can control chemically-induced diabetes in immune-deficient mice. These findings are comparable to those obtained from pluripotent cells. PD-L1 and PD-L2 expression by MSCs is upregulated under inflammatory conditions. Immunomodulation occurs due to the interaction between these ligands and PD-1 receptors on T lymphocytes. If this function is maintained after differentiation, life-long immunosuppression or encapsulation could be avoided. In the clinical setting, two sites can be used for transplantation of IPCs: the subcutaneous tissue and the omentum. A 2-stage procedure is required for the former and a laparoscopic procedure for the latter. For either site, cells should be transplanted within a scaffold, preferably one from fibrin. Several questions remain unanswered. Will the transplanted cells be affected by the antibodies involved in the pathogenesis of type 1 DM? What is the functional longevity of these cells following their transplantation? These issues have to be addressed before clinical translation is attempted. Graphical Abstract Bone marrow MSCs are isolated from the long bone of SD rats. Then they are expanded and through directed differentiation insulin-producing cells are formed. The differentiated cells are loaded onto a collagen scaffold. If one-stage transplantation is planned, a drug delivery system must be incorporated to ensure immediate oxygenation, promote vascularization and provide some growth factors. Some mechanisms involved in the immunomodulatory function of MSCs. These are implemented either by cell to cell contact or by the release of soluble factors. Collectively, these pathways results in an increase in T-regulatory cells.
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Uterine Stem Cells and Benign Gynecological Disorders: Role in Pathobiology and Therapeutic Implications. Stem Cell Rev Rep 2020; 17:803-820. [PMID: 33155150 DOI: 10.1007/s12015-020-10075-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2020] [Indexed: 12/15/2022]
Abstract
Stem cells in the endometrium and myometrium possess an immense regenerative potential which is necessary to maintain the menstrual cycle and support pregnancy. These cells, as well as bone marrow stem cells, have also been implicated in the development of common benign gynecological disorders including leiomyomas, endometriosis and adenomyosis. Current evidence suggests the conversion of uterine stem cells to tumor initiating stem cells in leiomyomas, endometriosis stem cells, and adenomyosis stem cells, acquiring genetic and epigenetic alterations for the progression of each benign condition. In this comprehensive review, we aim to summarize the progress that has been made to characterize the involvement of stem cells in the pathogenesis of benign gynecologic conditions which, despite their enormous burden, are not yet fully understood. We focus on the stem cell characteristics and aberrations that contribute to the development of benign gynecological disorders and the possible clinical implications of what is known so far. Lastly, we discuss the role of uterine stem cells in the setting of regenerative medicine, particularly in the treatment of Asherman syndrome.Graphical abstract.
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Noory P, Navid S, Zanganeh BM, Talebi A, Borhani-Haghighi M, Gholami K, Manshadi MD, Abbasi M. Human Menstrual Blood Stem Cell-Derived Granulosa Cells Participate in Ovarian Follicle Formation in a Rat Model of Premature Ovarian Failure In Vivo. Cell Reprogram 2020; 21:249-259. [PMID: 31596622 DOI: 10.1089/cell.2019.0020] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
We recently reported the application of human menstrual blood stem cells' (HuMenSCs) transplantation as a treatment modality in a rat model of premature ovarian failure (POF). We continued to investigate further in this respect. Female rats were injected intraperitoneally with 36 mg/kg busulfan. HuMenSCs were obtained, grown, and analyzed for immunophenotypic features at passage three. The cells were labeled with CM-Dil and infused into the rats. There were four groups: normal, negative control, treatment, and Sham. One month after treatment, the ovaries were collected and weighed. Histological sections were prepared from the ovary and HuMenSCs were tracking. Subsequently, we examined the changes of expression of Bax and B cell lymphoma 2 (Bcl2) genes by real-time polymerase chain reaction assay. One month after HuMenSCs transplantation, these cells were located in the ovarian interstitium and granulosa cells (GCs). The number of TUNEL-positive cells significantly decreased in the treatment group. Also the expression level of Bax genes, unlike Bcl2 gene, significantly decreased compared with negative and sham groups. In our study, HuMenSCs were tracked in ovarian tissues within 2 months after transplantation, and they differentiated into GCs. Therefore, the use of these cells can be a practical and low-cost method for the treatment of POF patients.
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Affiliation(s)
- Parastoo Noory
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shadan Navid
- Department of Anatomy, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Bagher Minaee Zanganeh
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Talebi
- School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.,Clinical Research Development Unit, Bahar Hospital, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Maryam Borhani-Haghighi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Keykavos Gholami
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Marjan Dehghan Manshadi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Abbasi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Functional β-Cell Differentiation of Small-Tail Han Sheep Pancreatic Mesenchymal Stem Cells and the Therapeutic Potential in Type 1 Diabetic Mice. Pancreas 2020; 49:947-954. [PMID: 32658079 DOI: 10.1097/mpa.0000000000001604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES This study aims to investigate the characteristics of sheep pancreatic mesenchymal stem cells (PSCs) and therapeutic potential of differentiated β-like cells in streptozotocin-induced diabetic mice. METHODS Pancreatic mesenchymal stem cells were isolated from 3- to 4-month-old sheep embryos, and their biological characteristics were explored. The function and therapeutic potential of differentiated β-like insulin-producing cells were also investigated in vitro and in vivo. Differentiated cells were identified through dithizone staining and immunofluorescence staining. Insulin secretion was analyzed using an enzyme-linked immunosorbent assay kit. The preliminary therapeutic potential of induced β-like cells in diabetic mice was detected by blood glucose and body weight. RESULTS Primary PSCs were isolated and subcultured up to passage 36. Immunofluorescence staining presented PSC-expressed important markers such as Pdx1, Nkx6-1, Ngn3, and Nestin. Primary PSCs could be induced into functional pancreatic β-like islet cells with a 3-step protocol. The induced β-like islet cells could ameliorate blood glucose in diabetic mice. CONCLUSIONS The method proposed for generating pancreatic islet β cells provided a preliminary phenotypic investigation of induced cell treatment in diabetic mice, and also laid a foundation in the identification of pharmaceutical targets to treat insulin-dependent diabetes.
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Bozorgmehr M, Gurung S, Darzi S, Nikoo S, Kazemnejad S, Zarnani AH, Gargett CE. Endometrial and Menstrual Blood Mesenchymal Stem/Stromal Cells: Biological Properties and Clinical Application. Front Cell Dev Biol 2020; 8:497. [PMID: 32742977 PMCID: PMC7364758 DOI: 10.3389/fcell.2020.00497] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 05/25/2020] [Indexed: 12/11/2022] Open
Abstract
A highly proliferative mesenchymal stem/stromal cell (MSC) population was recently discovered in the dynamic, cyclically regenerating human endometrium as clonogenic stromal cells that fulfilled the International Society for Cellular Therapy (ISCT) criteria. Specific surface markers enriching for clonogenic endometrial MSC (eMSC), CD140b and CD146 co-expression, and the single marker SUSD2, showed their perivascular identity in the endometrium, including the layer which sheds during menstruation. Indeed, cells with MSC properties have been identified in menstrual fluid and commonly termed menstrual blood stem/stromal cells (MenSC). MenSC are generally retrieved from menstrual fluid as plastic adherent cells, similar to bone marrow MSC (bmMSC). While eMSC and MenSC share several biological features with bmMSC, they also show some differences in immunophenotype, proliferation and differentiation capacities. Here we review the phenotype and functions of eMSC and MenSC, with a focus on recent studies. Similar to other MSC, eMSC and MenSC exert immunomodulatory and anti-inflammatory impacts on key cells of the innate and adaptive immune system. These include macrophages, T cells and NK cells, both in vitro and in small and large animal models. These properties suggest eMSC and MenSC as additional sources of MSC for cell therapies in regenerative medicine as well as immune-mediated disorders and inflammatory diseases. Their easy acquisition via an office-based biopsy or collected from menstrual effluent makes eMSC and MenSC attractive sources of MSC for clinical applications. In preparation for clinical translation, a serum-free culture protocol was established for eMSC which includes a small molecule TGFβ receptor inhibitor that prevents spontaneous differentiation, apoptosis, senescence, maintains the clonogenic SUSD2+ population and enhances their potency, suggesting potential for cell-therapies and regenerative medicine. However, standardization of MenSC isolation protocols and culture conditions are major issues requiring further research to maximize their potential for clinical application. Future research will also address crucial safety aspects of eMSC and MenSC to ensure these protocols produce cell products free from tumorigenicity and toxicity. Although a wealth of data on the biological properties of eMSC and MenSC has recently been published, it will be important to address their mechanism of action in preclinical models of human disease.
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Affiliation(s)
- Mahmood Bozorgmehr
- Reproductive Immunology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Shanti Gurung
- Centre for Reproductive Health, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - Saeedeh Darzi
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Shohreh Nikoo
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Somaieh Kazemnejad
- Nanobitechnology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Amir-Hassan Zarnani
- Reproductive Immunology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Caroline E. Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
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20
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Xu B, Yuan FZ, Lin L, Ye J, Fan BS, Zhang JY, Yang M, Jiang D, Jiang WB, Wang X, Yu JK. The Higher Inherent Therapeutic Potential of Biomaterial-Based hDPSCs and hEnSCs for Pancreas Diseases. Front Bioeng Biotechnol 2020; 8:636. [PMID: 32676499 PMCID: PMC7333240 DOI: 10.3389/fbioe.2020.00636] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 05/26/2020] [Indexed: 12/22/2022] Open
Abstract
Human endometrial stem cells (hEnSCs), dental pulp stem cells (hDPSCs) and adipose tissue-derived stem cells (hADSCs) are considered to be the promising candidates for the treatment of pancreas diseases. The prognosis is better with in situ injection of mesenchymal stem cells (MSCs) to the damaged pancreas compared with intravenous injection. However, the clinical application of these cells are limited, due to poor engraftment of transplanted cells after delivery. On the other hand, understanding the role of the biomaterials in cell therapy is essential to promote the therapeutic effects of MSCs. Matrigel, a basement membrane matrix biomaterial, is rich in laminin and collagen IV. The aim of this study is to investigate the difference of biological characteristics of hEnSCs, hDPSCs and hADSCs in vitro and their survival situation with Matrigel post intrapancreatic transplantation in vivo. Our findings showed, firstly, there was no significant difference in morphology and immunophenotype of these MSCs. Secondly, the biological properties, including cell proliferation, the ability of adipogenic and osteogenic differentiation and the mRNA expression levels of pancreas development-related genes, have been showed distinct difference among these MSCs. Thirdly, Matrigel can improve the survival of MSCs in vivo, especially for Matrigel-based hDPSCs and Matrigel-based hEnSCs in pancreas parenchyma of SD rats. These results suggest that hDPSCs and hEnSCs are with the greater inherent therapeutic potential for pancreas diseases compared with hADSCs.
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Affiliation(s)
- Bingbing Xu
- Knee Surgery Department of the Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
| | - Fu-Zhen Yuan
- Knee Surgery Department of the Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
| | - Lin Lin
- Knee Surgery Department of the Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
| | - Jing Ye
- Knee Surgery Department of the Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
| | - Bao-Shi Fan
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Ji-Ying Zhang
- Knee Surgery Department of the Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
| | - Meng Yang
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Dong Jiang
- Knee Surgery Department of the Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
| | - Wen-Bo Jiang
- Clinical Translational R&D Center of 3D Printing Technology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xing Wang
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics & Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jia-Kuo Yu
- Knee Surgery Department of the Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
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21
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Basal characterization and in vitro differentiation of putative stem cells derived from the adult mouse ovary. In Vitro Cell Dev Biol Anim 2020; 56:59-66. [PMID: 31900800 DOI: 10.1007/s11626-019-00411-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 10/14/2019] [Indexed: 10/25/2022]
Abstract
Lately, stem cell approaches have provided new information on reproductive organ function and additionally recommended novel treatment possibilities. The type(s) and differentiation potential of stem cells present in the mammalian ovary are largely unknown; while oogonial stem cells have been reported, we explored the possibility that multipotent stem cells may reside in the ovary and have wide differentiation potential. In this experimental study, homogenates of whole mouse ovaries were sorted using the stem cell surface markers stem cell antigen-1 and stage specific embryonic antigen-1/CD15. Viable double-positive cells 3-10 μm in diameter were evaluated immediately after sorting and after culture using differentiation conditions. Ovarian-derived stem cells were differentiated into the three main cell types: adipocytes, chondrocytes, or osteocytes. The subsequent culture was performed in media containing bone morphogenetic protein 4 (BMP-4) and/or retinoic acid (RA). RA, BMP-4 or the two agents in combination, consistently stimulated germ cell gene expression. RA treatment strongly stimulated germline gene expression and also the development of cells that were morphologically reminiscent of oocytes. The germ cell genes Dazl, Ddx4, Figla, Gdf-9, Nobox, Prdm9, and Sycp-1 were all detected at low levels. Remarkably, treatment with BMP-4 alone significantly increased protein expression of the granulosa cell product anti-Müllerian hormone (AMH). We have shown that an inclusive isolation protocol results in the consistent derivation of multipotent stem cells from the adult ovary; these cells can be differentiated towards the germ cell fate (RA alone), somatic ovarian cell fate as indicated by AMH production (BMP-4 alone), or classical mesenchymal cell types. Taken together, these data suggest the presence of multipotent mesenchymal stem cells in the murine ovary.
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22
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Ohta S, Ikemoto T, Wada Y, Saito Y, Yamada S, Imura S, Morine Y, Shimada M. A change in the zinc ion concentration reflects the maturation of insulin-producing cells generated from adipose-derived mesenchymal stem cells. Sci Rep 2019; 9:18731. [PMID: 31822724 PMCID: PMC6904733 DOI: 10.1038/s41598-019-55172-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 11/25/2019] [Indexed: 12/15/2022] Open
Abstract
The generation of insulin-producing cells (IPCs) from pluripotent stem cells could be a breakthrough treatment for type 1 diabetes. However, development of new techniques is needed to exclude immature cells for clinical application. Dithizone staining is used to evaluate IPCs by detecting zinc. We hypothesised that zinc ion (Zn2+) dynamics reflect the IPC maturation status. Human adipose-derived stem cells were differentiated into IPCs by our two-step protocol using two-dimensional (2D) or 3D culture. The stimulation indexes of 2D -and 3D-cultured IPCs on day 21 were 1.21 and 3.64 (P < 0.05), respectively. The 3D-cultured IPCs were stained with dithizone during culture, and its intensity calculated by ImageJ reached the peak on day 17 (P < 0.05). Blood glucose levels of streptozotocin-induced diabetic nude mice were normalised (4/4,100%) after transplantation of 96 3D-cultured IPCs. Zn2+ concentration changes in the medium of 3D cultures had a negative value in the early period and a large positive value in the latter period. This study suggests that Zn2+ dynamics based on our observations and staining of zinc transporters have critical roles in the differentiation of IPCs, and that their measurement might be useful to evaluate IPC maturation as a non-destructive method.
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Affiliation(s)
- Shogo Ohta
- Department of Digestive and Transplant Surgery, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
| | - Tetsuya Ikemoto
- Department of Digestive and Transplant Surgery, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
| | - Yuma Wada
- Department of Digestive and Transplant Surgery, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
| | - Yu Saito
- Department of Digestive and Transplant Surgery, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
| | - Shinichiro Yamada
- Department of Digestive and Transplant Surgery, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
| | - Satoru Imura
- Department of Digestive and Transplant Surgery, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
| | - Yuji Morine
- Department of Digestive and Transplant Surgery, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
| | - Mitsuo Shimada
- Department of Digestive and Transplant Surgery, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
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Using Mesenchymal Stem Cells to Treat Female Infertility: An Update on Female Reproductive Diseases. Stem Cells Int 2019; 2019:9071720. [PMID: 31885630 PMCID: PMC6925937 DOI: 10.1155/2019/9071720] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 11/15/2019] [Accepted: 11/21/2019] [Indexed: 12/18/2022] Open
Abstract
Female infertility impacts the quality of life and well-being of affected individuals and couples. Female reproductive diseases, such as primary ovarian insufficiency, polycystic ovary syndrome, endometriosis, fallopian tube obstruction, and Asherman syndrome, can induce infertility. In recent years, translational medicine has developed rapidly, and clinical researchers are focusing on the treatment of female infertility using novel approaches. Owing to the advantages of convenient samples, abundant sources, and avoidable ethical issues, mesenchymal stem cells (MSCs) can be applied widely in the clinic. This paper reviews recent advances in using four types of MSCs, bone marrow stromal cells, adipose-derived stem cells, menstrual blood mesenchymal stem cells, and umbilical cord mesenchymal stem cells. Each of these have been used for the treatment of ovarian and uterine diseases, and provide new approaches for the treatment of female infertility.
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24
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Reig A, Mamillapalli R, Coolidge A, Johnson J, Taylor HS. Uterine Cells Improved Ovarian Function in a Murine Model of Ovarian Insufficiency. Reprod Sci 2019; 26:1633-1639. [PMID: 31530098 PMCID: PMC6949960 DOI: 10.1177/1933719119875818] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Primary ovarian insufficiency (POI) is defined as ovarian dysfunction in women younger than 40 years. It affects 1% of the women in this age-group and can occur iatrogenically after chemotherapy. Stem cells have been used in attempt to restore ovarian function in POI. In particular, endometrial mesenchymal stem cells (eMSCs) are easily obtainable in humans and have shown great potential for regenerative medicine. Here, we studied the potential for uterine cell (UC) suspensions containing eMSCs to improve ovarian function in a murine model of chemotherapy-induced POI. Green fluorescent protein (GFP)-labeled UC or phosphate-buffered solution (PBS) was delivered intravenously after chemotherapy. There was a significant increase in oocytes production and serum anti-Müllerian hormone concentrations after 6 weeks, as well as a 19% higher body mass in UC-treated mice. Similarly, we observed an increased number of pups in mice treated with UC than in mice treated with PBS. None of the oocytes or pups incorporated GFP, suggesting that there was no contribution of these stem cells to the oocyte pool. We conclude that treatment with UC indirectly improved ovarian function in mice with chemotherapy-induced POI. Furthermore, our study suggests that endometrial stem cell therapy may be beneficial to young women who undergo ovotoxic chemotherapy.
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Affiliation(s)
- Andres Reig
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Ramanaiah Mamillapalli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Alexis Coolidge
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Joshua Johnson
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Hugh S. Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
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25
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Cao M, Chan RWS, Cheng FHC, Li J, Li T, Pang RTK, Lee CL, Li RHW, Ng EHY, Chiu PCN, Yeung WSB. Myometrial Cells Stimulate Self-Renewal of Endometrial Mesenchymal Stem-Like Cells Through WNT5A/β-Catenin Signaling. Stem Cells 2019; 37:1455-1466. [PMID: 31414525 DOI: 10.1002/stem.3070] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 07/15/2019] [Accepted: 07/21/2019] [Indexed: 01/01/2023]
Abstract
Human endometrium undergoes cycles of proliferation and differentiation throughout the reproductive years of women. The endometrial stem/progenitor cells contribute to this regenerative process. They lie in the basalis layer of the endometrium next to the myometrium. We hypothesized that human myometrial cells provide niche signals regulating the activities of endometrial mesenchymal stem-like cells (eMSCs). In vitro coculture of myometrial cells enhanced the colony-forming and self-renewal ability of eMSCs. The cocultured eMSCs retained their multipotent characteristic and exhibited a greater total cell output when compared with medium alone culture. The expression of active β-catenin in eMSCs increased significantly after coculture with myometrial cells, suggesting activation of WNT/β-catenin signaling. Secretory factors in spent medium from myometrial cell culture produced the same stimulatory effects on eMSCs. The involvement of WNT/β-catenin signaling in self-renewal of eMSCs was confirmed with the use of WNT activator (Wnt3A conditioned medium) and WNT inhibitors (XAV939 and inhibitor of Wnt Production-2 [IWP-2]). The myometrial cells expressed more WNT5A than other WNT ligands. Recombinant WNT5A stimulated whereas anti-WNT5A antibody suppressed the colony formation, self-renewal, and T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcriptional activities of eMSCs. Moreover, eMSCs expressed FZD4 and LRP5. WNT5A is known to activate the canonical WNT signaling in the presence of these receptor components. WNT antagonist, DKK1, binds to LRP5/6. Consistently, DKK1 treatment nullified the stimulatory effect of myometrial cell coculture. In conclusion, our findings show that the myometrial cells are niche components of eMSCs, modulating the self-renewal activity of eMSCs by WNT5A-dependent activation of WNT/β-catenin signaling. Stem Cells 2019;37:1455-1466.
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Affiliation(s)
- Mingzhu Cao
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China.,Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Rachel W S Chan
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Fiona H C Cheng
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Jiangxue Li
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Tianqi Li
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Ronald T K Pang
- Shenzhen Key Laboratory Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen, People's Republic of China
| | - Cheuk-Lun Lee
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Shenzhen Key Laboratory Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen, People's Republic of China
| | - Raymond H W Li
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Shenzhen Key Laboratory Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen, People's Republic of China
| | - Ernest H Y Ng
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Shenzhen Key Laboratory Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen, People's Republic of China
| | - Philip C N Chiu
- Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Shenzhen Key Laboratory Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen, People's Republic of China
| | - William S B Yeung
- Shenzhen Key Laboratory Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen, People's Republic of China
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26
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Santamaria X, Mas A, Cervelló I, Taylor H, Simon C. Uterine stem cells: from basic research to advanced cell therapies. Hum Reprod Update 2019; 24:673-693. [PMID: 30239705 DOI: 10.1093/humupd/dmy028] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 08/04/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Stem cell research in the endometrium and myometrium from animal models and humans has led to the identification of endometrial/myometrial stem cells and their niches. This basic knowledge is beginning to be translated to clinical use for incurable uterine pathologies. Additionally, the implication of bone marrow-derived stem cells (BMDSCs) in uterine physiology has opened the field for the exploration of an exogenous and autologous source of stem cells. OBJECTIVE AND RATIONALE In this review, we outline the progress of endometrial and myometrial stem/progenitor cells in both human and mouse models from their characterization to their clinical application, indicating roles in Asherman syndrome, atrophic endometrium and tissue engineering, among others. SEARCH METHODS A comprehensive search of PubMed and Google Scholar up to December 2017 was conducted to identify peer-reviewed literature related to the contribution of bone marrow, endometrial and myometrial stem cells to potential physiological regeneration as well as their implications in pathologies of the human uterus. OUTCOMES The discovery and main characteristics of stem cells in the murine and human endometrium and myometrium are presented together with the relevance of their niches and cross-regulation. The current state of advanced stem cell therapy using BMDSCs in the treatment of Asherman syndrome and atrophic endometrium is analyzed. In the myometrium, the understanding of genetic and epigenetic defects that result in the development of tumor-initiating cells in the myometrial stem niche and thus contribute to the growth of uterine leiomyoma is also presented. Finally, recent advances in tissue engineering based on the creation of novel three-dimensional scaffolds or decellularisation open up new perspectives for the field of uterine transplantation. WIDER IMPLICATIONS More than a decade after their discovery, the knowledge of uterine stem cells and their niches is crystalising into novel therapeutic approaches aiming to treat with cells those conditions that cannot be cured with drugs, particularly the currently incurable uterine pathologies. Additional work and improvements are needed, but the basis has been formed for this therapeutic application of uterine cells.
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Affiliation(s)
- Xavier Santamaria
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Reproductive Medicine Department, IVI Barcelona, Barcelona, Spain.,Department of Obstetrics and Gynecology, Biomedical Research Group in Gynecology, Vall Hebron Institut de Recerca, Barcelona, Spain
| | - Aymara Mas
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Department of Obstetrics and Gynecology, Reproductive Medicine Research Group, La Fe Health Research Institute, Valencia, Spain
| | - Irene Cervelló
- Department of Obstetrics and Gynecology, Fundación Instituto Valenciano de Infertilidad (FIVI), and Instituto Universitario IVI/INCLIVA, Valencia, Spain
| | - Hugh Taylor
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Carlos Simon
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Department of Pediatrics, Obstetrics, and Gynecology, Valencia University and INCLIVA, Valencia, Spain.,Department of Obstetrics and Gynecology, Stanford University, Stanford, CA, USA
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Kumar SA, Delgado M, Mendez VE, Joddar B. Applications of stem cells and bioprinting for potential treatment of diabetes. World J Stem Cells 2019; 11:13-32. [PMID: 30705712 PMCID: PMC6354103 DOI: 10.4252/wjsc.v11.i1.13] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/26/2018] [Accepted: 01/05/2019] [Indexed: 02/06/2023] Open
Abstract
Currently, there does not exist a strategy that can reduce diabetes and scientists are working towards a cure and innovative approaches by employing stem cell-based therapies. On the other hand, bioprinting technology is a novel therapeutic approach that aims to replace the diseased or lost β-cells, insulin-secreting cells in the pancreas, which can potentially regenerate damaged organs such as the pancreas. Stem cells have the ability to differentiate into various cell lines including insulin-producing cells. However, there are still barriers that hamper the successful differentiation of stem cells into β-cells. In this review, we focus on the potential applications of stem cell research and bioprinting that may be targeted towards replacing the β-cells in the pancreas and may offer approaches towards treatment of diabetes. This review emphasizes on the applicability of employing both stem cells and other cells in 3D bioprinting to generate substitutes for diseased β-cells and recover lost pancreatic functions. The article then proceeds to discuss the overall research done in the field of stem cell-based bioprinting and provides future directions for improving the same for potential applications in diabetic research.
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Affiliation(s)
- Shweta Anil Kumar
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
| | - Monica Delgado
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
| | - Victor E Mendez
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
| | - Binata Joddar
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
- Border Biomedical Research Center, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States.
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28
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Manshadi MD, Navid S, Hoshino Y, Daneshi E, Noory P, Abbasi M. The effects of human menstrual blood stem cells-derived granulosa cells on ovarian follicle formation in a rat model of premature ovarian failure. Microsc Res Tech 2018; 82:635-642. [PMID: 30582244 DOI: 10.1002/jemt.23120] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/16/2018] [Accepted: 08/03/2018] [Indexed: 12/22/2022]
Abstract
Many studies have reported that human endometrial mesenchymal stem cells (HuMenSCs) are capable of repairing damaged tissues. The aim of the present study was to investigate the effects of HuMenSCs transplantation as a treatment modality in premature ovarian failure (POF) associated with chemotherapy-induced ovarian damage. HuMenSCs were isolated from menstrual blood samples of five women. After the in vitro culture of HuMenSCs, purity of the cells was assessed by cytometry using CD44, CD90, CD34, and CD45 FITC conjugate antibody. Twenty-four female Wistar rats were randomly divided into four groups: negative control, positive control, sham, and treatment groups. The rat models of POF used in our study were established by injecting busulfan intraperitoneally into the rats during the first estrus cycle. HuMenSCs were transplanted by injection via the tail vein into the POF-induced rats. Four weeks after POF induction, ovaries were collected and the levels of Amh, Fst, and Fshr expression in the granulosa cell (GC) layer, as well as plasma estradiol (E2) and progesterone (P4) levels were evaluated. Moreover, migration and localization of DiI-labeled HuMenSCs were detected, and the labeled cells were found to be localized in GCs layer of immature follicles. In addition to DiI-labelled HuMenSCs tracking, increased levels of expression of Amh and Fshr and Fst, and the high plasma levels of E2 and P4 confirmed that HuMenSC transplantation had a significant effect on follicle formation and ovulation in the treatment group compared with the negative control (POF) group.
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Affiliation(s)
- Marjan D Manshadi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shadan Navid
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Department of Anatomy, School of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Yumi Hoshino
- Laboratory of Reproductive Endocrinology, Graduate School of Biosphere Science, Hiroshima University, Hiroshima, Japan
| | - Erfan Daneshi
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Parastoo Noory
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Abbasi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Lv H, Hu Y, Cui Z, Jia H. Human menstrual blood: a renewable and sustainable source of stem cells for regenerative medicine. Stem Cell Res Ther 2018; 9:325. [PMID: 30463587 PMCID: PMC6249727 DOI: 10.1186/s13287-018-1067-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023] Open
Abstract
Stem cells (SCs) play an important role in autologous and even allogenic applications. Menstrual blood discharge has been identified as a valuable source of SCs which are referred to as menstrual blood-derived stem cells (MenSCs). Compared to SCs from bone marrow and adipose tissues, MenSCs come from body discharge and obtaining them is non-invasive to the body, they are easy to collect, and there are no ethical concerns. There is, hence, a growing interest in the functions of MenSCs and their potential applications in regenerative medicine. This review presents recent progress in research into MenSCs and their potential application. Clinical indications of using MenSCs for various regenerative medicine applications are emphasized, and future research is recommended to accelerate clinical applications of MenSCs.
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Affiliation(s)
- Haining Lv
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Graduate School of Peking Union Medical College, 321 Zhongshan Road, Nanjing, China
| | - Yali Hu
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Graduate School of Peking Union Medical College, 321 Zhongshan Road, Nanjing, China.
| | - Zhanfeng Cui
- Tissue Engineering Group, Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, ORCRB, Roosevelt Drive, Headington, Oxford, OX3 7DQ, UK
| | - Huidong Jia
- Tissue Engineering Group, Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, ORCRB, Roosevelt Drive, Headington, Oxford, OX3 7DQ, UK.
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30
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Endometrial Stem Cell Markers: Current Concepts and Unresolved Questions. Int J Mol Sci 2018; 19:ijms19103240. [PMID: 30347708 PMCID: PMC6214006 DOI: 10.3390/ijms19103240] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 09/07/2018] [Accepted: 10/10/2018] [Indexed: 02/07/2023] Open
Abstract
The human endometrium is a highly regenerative organ undergoing over 400 cycles of shedding and regeneration over a woman’s lifetime. Menstrual shedding and the subsequent repair of the functional layer of the endometrium is a process unique to humans and higher-order primates. This massive regenerative capacity is thought to have a stem cell basis, with human endometrial stromal stem cells having already been extensively studied. Studies on endometrial epithelial stem cells are sparse, and the current belief is that the endometrial epithelial stem cells reside in the terminal ends of the basalis glands at the endometrial/myometrial interface. Since almost all endometrial pathologies are thought to originate from aberrations in stem cells that regularly regenerate the functionalis layer, expansion of our current understanding of stem cells is necessary in order for curative treatment strategies to be developed. This review critically appraises the postulated markers in order to identify endometrial stem cells. It also examines the current evidence supporting the existence of epithelial stem cells in the human endometrium that are likely to be involved both in glandular regeneration and in the pathogenesis of endometrial proliferative diseases such as endometriosis and endometrial cancer.
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31
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Anjum MS, Mehmood A, Mahmood F, Ali M, Tarrar MN, Khan SN, Riazuddin S. In vitro preconditioning of insulin-producing cells with growth factors improves their survival and ability to release insulin. J Biosci 2018; 43:649-659. [PMID: 30207311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Glucose-induced oxidative stress in the diabetic pancreas directly affects viability and the consequent therapeutic outcome of transplanted stem cells. Pretreatment of stem cells with growth factors induces tolerance in them against various stresses (hypoxia, thermal or hyperglycaemic). This study investigated the effect of pretreatment on insulin-producing cells (IPCs) differentiated from adipose-derived mesenchymal stem cells (ADMSCs), with a combination of stromal cell-derived factor 1 alpha (SDF1 α) and basic fibroblast growth factor (bFGF) against hyperglycaemic stress (17 or 33 mM glucose). The results showed that IPCs pretreated with a combination of SDF1α and bFGF exhibited maximally alleviated apoptosis, senescence and cell damage with a concomitantly increased release of insulin, enhanced cell proliferation and greater upregulation of Insulin 1, Insulin 2, Ngn3, Pdx1 and Nkx6.2 when stressed with 33 mM glucose. These findings may offer an improved therapeutic outcome for the treatment of diabetes.
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Affiliation(s)
- Muhammad Sohail Anjum
- National Centre of Excellence in Molecular Biology, University of Punjab, 87-West Canal Bank Road, Lahore, Pakistan
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32
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Wu Q, Wang Q, Li Z, Li X, Zang J, Wang Z, Xu C, Gong Y, Cheng J, Li H, Shen G, Dong C. Human menstrual blood-derived stem cells promote functional recovery in a rat spinal cord hemisection model. Cell Death Dis 2018; 9:882. [PMID: 30158539 PMCID: PMC6115341 DOI: 10.1038/s41419-018-0847-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 06/25/2018] [Accepted: 06/27/2018] [Indexed: 12/21/2022]
Abstract
Spinal cord injury (SCI) is associated with a dismal prognosis including severe voluntary motor and sensory deficits in the presence of the current therapies, thus new and efficient treatment strategies are desperately required. Along with several advantages, such as easy accessibility, high-yield, potential of enormous proliferation, menstrual blood-derived mesenchymal stem cells (MenSCs) have been proposed as a promising strategy in regeneration medicine. In this study, the MenSCs were transplanted into incomplete thoracic (T10) spinal cord injury (SCI) rats, all rats were sacrificed at 7, 14, and 28 days after surgery. Based on the results, we found that MenSCs transplantation improved the hind limb motor function. Besides, H&E staining showed that MenSCs treatment markedly reduced cavity formation in the lesion site. Furthermore, treatment by MenSCs showed more MAP2-positive mature neurons, as well as axonal regeneration manifested by NF-200 and less expression of chondroitin sulfate proteoglycans (CSPGs) than the non-treatment in the lesion site. Additionally, immunofluorescence, Western blot, and qRT-PCR methods showed that levels of brain-derived neurotrophic factor (BDNF) were significantly higher in the injured spinal cord after implantation of MenSCs. Results of qRT-PCR indicated that inflammatory factors, including TNF-α and IL-1β were inhibited after MenSCs transplantation. The improved motor function of hind limb and the increased cell body area of motor neurons were suppressed by blocking of the BDNF-TrkB signaling. It was eventually revealed that MenSCs implantation had beneficial therapeutic effects on the rehabilitation of the rat spinal cord hemisection model, mainly by enhancing the expression of BDNF. MenSCs transplantation may provide a novel therapeutic strategy for patients with SCI in the future.
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Affiliation(s)
- Qinfeng Wu
- Department of Anatomy, Medical School of Nantong University, Laboratory Animal Center of Nantong University, Nantong, Jiangsu Province, 226001, China.,Department of Rehabilitation Medicine, Suzhou Hospital affiliated to Nanjing Medical University, Suzhou Science & Technology Town Hospital, 215153, Suzhou, Jiangsu Province, China
| | - Qinghua Wang
- Department of Anatomy, Medical School of Nantong University, Laboratory Animal Center of Nantong University, Nantong, Jiangsu Province, 226001, China
| | - Zhangjie Li
- Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, 226001, Nantong, Jiangsu Province, China.,Department of Rehabilitation Medicine, Zhangjiagang First People's Hospital, 215600, Zhangjiagang, Jiangsu Province, China
| | - Xiangzhe Li
- Department of Rehabilitation Medicine, Suzhou Hospital affiliated to Nanjing Medical University, Suzhou Science & Technology Town Hospital, 215153, Suzhou, Jiangsu Province, China
| | - Jing Zang
- Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, 226001, Nantong, Jiangsu Province, China
| | - Zhangwei Wang
- Department of Anatomy, Medical School of Nantong University, Laboratory Animal Center of Nantong University, Nantong, Jiangsu Province, 226001, China
| | - Chen Xu
- Department of Anatomy, Medical School of Nantong University, Laboratory Animal Center of Nantong University, Nantong, Jiangsu Province, 226001, China
| | - Yujia Gong
- Department of Anatomy, Medical School of Nantong University, Laboratory Animal Center of Nantong University, Nantong, Jiangsu Province, 226001, China
| | - Jiaqi Cheng
- Department of Anatomy, Medical School of Nantong University, Laboratory Animal Center of Nantong University, Nantong, Jiangsu Province, 226001, China
| | - Haoming Li
- Department of Anatomy, Medical School of Nantong University, Laboratory Animal Center of Nantong University, Nantong, Jiangsu Province, 226001, China
| | - Guangyu Shen
- Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, 226001, Nantong, Jiangsu Province, China
| | - Chuanming Dong
- Department of Anatomy, Medical School of Nantong University, Laboratory Animal Center of Nantong University, Nantong, Jiangsu Province, 226001, China.
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33
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In vitro preconditioning of insulin-producing cells with growth factors improves their survival and ability to release insulin. J Biosci 2018. [DOI: 10.1007/s12038-018-9796-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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34
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Subbarao RB, Shivakumar SB, Choe YH, Son YB, Lee HJ, Ullah I, Jang SJ, Ock SA, Lee SL, Rho GJ. CD105 + Porcine Endometrial Stromal Mesenchymal Stem Cells Possess Differentiation Potential Toward Cardiomyocyte-Like Cells and Insulin-Producing β Cell-Like Cells In Vitro. Reprod Sci 2018; 26:669-682. [PMID: 29986624 DOI: 10.1177/1933719118786461] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Porcine mesenchymal stem cells (MSCs) are similar to human MSCs, hence considered a valuable model for assessing potential for cell therapy. Porcine adipose-derived MSCs (AD-MSCs) and endometrial stromal MSCs (EMSCs) displayed fibroblast-like morphology and were positive for MSC markers CD73, CD90, and CD105 and negative for hematopoietic markers CD34 and CD45. The EMSCs had similar or slightly higher growth rate compared to AD-MSCs, and similar percentage of cells of both EMSCs and AD-MSCs were at G0/G1 and G2/M phases; however, EMSCs had significantly ( P < .05) higher percentage of cells at S phase of cell cycle than AD-MSCs. Transdifferentiation ability to cardiomyocyte-like cells was confirmed in differentiated cells by the expression of lineage-specific marker genes such as DES, ACTA2, cTnT, and ACTC1 by real-time quantitative polymerase chain reaction (RT-qPCR). Furthermore, cardiomyocyte-specific protein markers cTnT and ACTC1 were expressed in completely differentiated cells. Endodermal differentiation capacity of EMSCs to pancreatic β cell-like cells was evident with the changes in morphology and the expression of β-cell-specific marker genes such as PDX1, GLUT2, SST, NKX6.1, PAX4, and NGN3 as analyzed by RT-qPCR. The differentiated cells secreted insulin and C-peptide upon glucose challenge and also they expressed insulin, PDX1, PAX4, NGN3, and GLUT2 at protein level as assessed by immunostaining confirming the successful differentiation to β cell-like cells. Porcine EMSCs possess all the characteristics of MSCs and are suitable model for studying molecular mechanisms of cellular differentiation.
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Affiliation(s)
- Raghavendra Baregundi Subbarao
- 1 Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Sharath Belame Shivakumar
- 1 Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Yong-Ho Choe
- 1 Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Young-Bum Son
- 1 Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Hyeon-Jeong Lee
- 1 Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Imran Ullah
- 1 Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Si-Jung Jang
- 1 Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Sun-A Ock
- 2 Animal Biotechnology Division, National Institute of Animal Science, RDA, Wanju-gun, Jeollabuk-do, Republic of Korea
| | - Sung-Lim Lee
- 1 Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Gyu-Jin Rho
- 1 Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju, Republic of Korea.,3 Research Institute of Life Sciences, Gyeongsang National University, Jinju, Republic of Korea
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35
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Qin W, Xiong Y, Chen J, Huang Y, Liu T. DC-CIK cells derived from ovarian cancer patient menstrual blood activate the TNFR1-ASK1-AIP1 pathway to kill autologous ovarian cancer stem cells. J Cell Mol Med 2018; 22:3364-3376. [PMID: 29566310 PMCID: PMC6010766 DOI: 10.1111/jcmm.13611] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 02/22/2018] [Indexed: 12/13/2022] Open
Abstract
Ovarian cancer stem cells (OCSCs) are highly carcinogenic and have very strong resistance to traditional chemotherapeutic drugs; therefore, they are an important factor in ovarian cancer metastasis and recurrence. It has been reported that dendritic cell (DC)-cytokine-induced killer (CIK) cells have significant killing effects on all cancer cells across many systems including the blood, digestive, respiratory, urinary and reproductive systems. However, whether DC-CIK cells can selectively kill OCSCs is currently unclear. In this study, we collected ovarian cancer patient menstrual blood (OCPMB) samples to acquire mononuclear cells and isolated DC-CIK cells in vitro. In addition, autologous CD44+/CD133+ OCSCs were isolated and used as target cells. The experimental results showed that when DC-CIK cells and OCSCs were mixed and cultured in vitro at ratios of 5:1, 10:1 and 50:1, the DC-CIK cells killed significant amounts of OCSCs, inhibited their invasion in vitro and promoted their apoptosis. The qPCR and Western blot results showed that DC-CIK cells stimulated high expression levels and phosphorylation of TNFR1, ASK1, AIP1 and JNK in OCSCs through the release of TNF-α. After the endogenous TNFR1 gene was knocked out in OCSCs using the CRISPR/Cas9 technology, the killing function of DC-CIK cells on target OCSCs was significantly attenuated. The results of the analyses of clinical samples suggested that the TNFR1 expression level was negatively correlated with ovarian cancer stage and prognosis. Therefore, we innovatively confirmed that DC-CIK cells derived from OCPMB could secret TNF-α to activate the expression of the TNFR1-ASK1-AIP1-JNK pathway in OCSCs and kill autologous OCSCs.
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Affiliation(s)
- Wenxing Qin
- Department of Clinical OncologyChangzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Ying Xiong
- Department of Gynaecology and ObstetricsXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Juan Chen
- Gongli Hospital Affiliated to the Second Military Medical University in Pudong New Area of Shanghai CityShanghaiChina
| | | | - Te Liu
- Shanghai Geriatric Institute of Chinese MedicineShanghai University of Traditional Chinese MedicineShanghaiChina
- Department of PathologyYale University School of MedicineNew HavenCTUSA
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Simoni M, Taylor HS. Therapeutic strategies involving uterine stem cells in reproductive medicine. Curr Opin Obstet Gynecol 2018; 30:209-216. [PMID: 29652725 DOI: 10.1097/gco.0000000000000457] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW The current review provides an update on recent advances in stem cell biology relevant to female reproduction. RECENT FINDINGS Stem cells are undifferentiated cells that often serve as a reservoir of cells to regenerate tissue in settings or injury or cell loss. The endometrium has progenitor stem cells that can replace all of the endometrium during each menstrual cycle. In addition, multipotent endometrial cells replace these progenitor cells when depleted. Recruitment of stem cells from outside of the uterus occurs in setting of increased demand such as ischemia or injury. Bone marrow-derived multipotent stem cells are recruited to the uterus by estrogen or injury-induced expression of the chemokine CXCL12. In the setting of overwhelming injury, especially in the setting of low estrogen levels, there may be insufficient stem cell recruitment to adequately repair the uterus resulting in conditions such as Asherman syndrome or other endometrial defects. In contrast, excessive recruitment of stem cells underlies endometriosis. Enhanced understanding of stem-cell mobilization, recruitment, and engraftment has created the possibility of improved therapy for endometrial defects and endometriosis through enhanced manipulation of stem-cell trafficking. Further, the normal endometrium is a rich source of multipotent stem cells that can be used for numerous applications in regenerative medicine beyond reproduction. SUMMARY A better understanding of reproductive stem-cell biology may allow improved treatment of endometrial disease such as Asherman syndrome and other endometrial receptivity defects. Inhibiting stem-cell mobilization may also be helpful in endometriosis therapy. Finally, endometrial derived multipotent stem cells may play a crucial role in cell therapy for regenerative medicine.
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Affiliation(s)
- Michael Simoni
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
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Ghobadi F, Rahmanifar F, Mehrabani D, Tamadon A, Dianatpour M, Zare S, Razeghian Jahromi I, Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran, Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran, Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran, Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran, Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran, Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran, Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Endometrial mesenchymal stem stromal cells in mature and immature sheep: An in vitro study. Int J Reprod Biomed 2018. [DOI: 10.29252/ijrm.16.2.83] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
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Ghobadi F, Rahmanifar F, Mehrabani D, Tamadon A, Dianatpour M, Zare S, Razeghian Jahromi I. Endometrial mesenchymal stem stromal cells in mature and immature sheep: An in vitro study. Int J Reprod Biomed 2018; 16:83-92. [PMID: 29675492 PMCID: PMC5899822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Endometrial mesenchymal stem stromal cells (EnMSCs) are critical for uterine function, repair, and regeneration. OBJECTIVE This study introduced isolation technique of EnMSCs and compared the characteristics of EnMSCs in mature and immature ewes. MATERIALS AND METHODS Endometrial tissue samples from the uterus of 10 ewes were collected from the slaughterhouse. Endometrial cells were isolated from tissue using cold incubation and then chopping and treating was performed with collagenase type I. Isolated cells were cultured in cell culture medium and then attached cells to flasks were harvested as EnMSCs and subcultured. To enumerate the cells, the population doubling time (PDT) was determined and 2.2×104 cells in passage 4 were seeded into 24-well culture plates to compare the growth curves of isolated cells. Reverse transcription polymerase chain reaction (RT-PCR) was performed for detection of CD34 and CD73 markers. The osteogenic and adipogenic potential of isolated cells were determined using differentiation tests. RESULTS EnMSCs adhered to the flasks and displayed spindle-shape. Based on findings of the cell count and the growth curves, the EnMSCs growth was significantly more prominent in immature ewes in comparison to mature sheep. The PDT of EnMSCs in immature ewes was about 21 hr whereas this time period was two times higher (45 hr) in mature sheep. RT-PCR analyses of EnMSCs were positive for CD73 and negative for CD34. EnMSCs were differentiated into osteoblasts and adipocytes. CONCLUSION Based on mesenchymal stem cells characters confirmed in EnMSCs, they can be a candidate for cell therapy and regenerative medicine.
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Affiliation(s)
- Farnaz Ghobadi
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Farhad Rahmanifar
- Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran.
| | - Davood Mehrabani
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Corresponding Author: Davood Mehrabani, Stem Cells Technology Research Center, 3rd Floor, Muhammad Rasulollah Research Tower, Shiraz University of Medical Sciences, Khalili Ave., Shiraz, Iran. , Tel: (+98) 71 36281547, Amin Tamadon, Stem Cells Technology Research Center, 3rd Floor, Muhammad Rasulollah Research Tower, Shiraz University of Medical Sciences, Khalili Ave., Shiraz, Iran. , Tel: (+98) 71 36281547
| | - Amin Tamadon
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Corresponding Author: Davood Mehrabani, Stem Cells Technology Research Center, 3rd Floor, Muhammad Rasulollah Research Tower, Shiraz University of Medical Sciences, Khalili Ave., Shiraz, Iran. , Tel: (+98) 71 36281547, Amin Tamadon, Stem Cells Technology Research Center, 3rd Floor, Muhammad Rasulollah Research Tower, Shiraz University of Medical Sciences, Khalili Ave., Shiraz, Iran. , Tel: (+98) 71 36281547
| | - Mehdi Dianatpour
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Human Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Shahrokh Zare
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Luo Y, Xu Y, Wang ZY, Li X, Xing WB, Zhang TC. The Synergy of Two Factors on Insulin Expression. Cell Reprogram 2018; 20:49-54. [PMID: 29303357 DOI: 10.1089/cell.2017.0026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
As a potential cure for diabetes, more and more attentions have been paid to organ transplants to replace insulin therapy. As a result, many researchers have explored out many programs to get insulin-producing cells (IPCs) to replace the defective β cells. Currently, more and more new induction methods are being proposed, and at the same time, more and more possible induction molecular mechanisms are being revealed. The purpose of this study was to explore whether and how the two factors pdx-1 and myocardin affected the differentiation of rat mesenchymal stem cells (rMSCs) into IPCs. In this study, we investigated the process of transfecting myocardin and/or pdx-1 in rMSCs in vitro. The results showed that rMSCs were able to secrete insulin after cotransfected with myocardin and pdx-1. At the same time, we explored the possible mechanism that myocardin and pdx-1 coinduced rMSCs into IPCs by forming a complex to promote the transcriptional activity of insulin. Our results may provide a theoretical basis to the study of islet transplantation in the future.
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Affiliation(s)
- Ying Luo
- 1 Institute of Biology and Medicine, Wuhan University of Science and Technology , Wuhan, China
| | - Yao Xu
- 1 Institute of Biology and Medicine, Wuhan University of Science and Technology , Wuhan, China
| | - Zhen-Yu Wang
- 1 Institute of Biology and Medicine, Wuhan University of Science and Technology , Wuhan, China
| | - Xi Li
- 1 Institute of Biology and Medicine, Wuhan University of Science and Technology , Wuhan, China
| | - Wei-Bing Xing
- 1 Institute of Biology and Medicine, Wuhan University of Science and Technology , Wuhan, China
| | - Tong-Cun Zhang
- 1 Institute of Biology and Medicine, Wuhan University of Science and Technology , Wuhan, China .,2 Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City, College of Biotechnology, Tianjin University of Science and Technology , Tianjin, China
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Liu Y, Tal R, Pluchino N, Mamillapalli R, Taylor HS. Systemic administration of bone marrow-derived cells leads to better uterine engraftment than use of uterine-derived cells or local injection. J Cell Mol Med 2018; 22:67-76. [PMID: 28782281 PMCID: PMC5742714 DOI: 10.1111/jcmm.13294] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 05/31/2017] [Indexed: 12/17/2022] Open
Abstract
Stem cells are recruited to the uterus where they differentiate into endometrial cells and have been suggested as potential therapy for uterine injury such as Asherman's syndrome. However, it is unknown whether local intrauterine injection may result in better stem cell engraftment of the uterus compared with systemic administration, and whether uterine-derived cells (UDCs) may confer an advantage over BM-derived cells (BMDCs). Mice underwent local injury to a single uterine horn. Green fluorescent protein (GFP)-expressing BMDCs, UDCs or saline (control) were injected either intravenously or locally (uterine lumen) into wild-type recipients. Two or 3 weeks post-transplant, uterine tissues were collected for fluorescence-activated cell sorting (FACS) and immunohistochemistry/immunofluorescence studies. Mice injected intravenously with BMDCs or UDCs had increased GFP+ cells recruitment to the non-injured or injured uterus compared to those injected locally. No significant differences were noted in GFP+ cell recruitment to the injured versus non-injured horn. In addition, systemic injection of BMDCs led to greater recruitment of GFP+ cells at 2 weeks and 3 weeks compared with UDCs. Immunohistochemical staining demonstrated that GFP+ cells were found in stroma but not in epithelium or blood vessels. Immunofluorescence analysis revealed that GFP+ cells were mostly CD45-negative, and negative for CD31 and cytokeratin, confirming their stromal identity. In conclusion, the systemic route of administration results in better recruitment of BMDCs or UDCs to the injured uterus than local injection. In addition, BMDCs recruitment to the uterus is greater than UDCs. These findings inform the development of stem cell-based therapies targeting the uterus.
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Affiliation(s)
- Ying Liu
- Department of Obstetrics, Gynecology & Reproductive SciencesYale University School of MedicineNew HavenCTUSA
- Present address:
Department of Reproductive MedicineBeijing Obstetrics and Gynecology HospitalCapital Medical UniversityBeijingChina
| | - Reshef Tal
- Department of Obstetrics, Gynecology & Reproductive SciencesYale University School of MedicineNew HavenCTUSA
| | - Nicola Pluchino
- Department of Obstetrics, Gynecology & Reproductive SciencesYale University School of MedicineNew HavenCTUSA
| | - Ramanaiah Mamillapalli
- Department of Obstetrics, Gynecology & Reproductive SciencesYale University School of MedicineNew HavenCTUSA
| | - Hugh S. Taylor
- Department of Obstetrics, Gynecology & Reproductive SciencesYale University School of MedicineNew HavenCTUSA
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In-vitro construction of endometrial-like epithelium using CD146 + mesenchymal cells derived from human endometrium. Reprod Biomed Online 2017; 35:241-252. [PMID: 28668272 DOI: 10.1016/j.rbmo.2017.05.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 05/03/2017] [Accepted: 05/04/2017] [Indexed: 02/05/2023]
Abstract
Endometrial CD146+ cells were purified, using magnetic activated cell sorting, and then embedded and cultured in a collagen-matrigel scaffold on top of myometrial smooth muscle cells for 10 days. At the end of culture period, the differentiation and formation of the epithelial-like cells were confirmed by morphological and ultrastructural evaluations, and analysis by reverse transcription polymerase chain reaction of the specific expression of genes: osteopontin (SPP1), matrix metalloproteinase 2, zonula occludens 1, laminin alpha 2 and collagen type IV; and by western blotting of CD9 protein. The results showed that the human endometrial mesenchymal CD146+ cells were able to produce endometrial glandular tube-like structures in vitro. Ultrastructural observation revealed some projections on the apical surfaces, appearance of basal lamina-like structures on the basal surface, and tight junctions and desmosomes on the lateral surfaces of the epithelial-like cells. The expression of studied genes at RNA level and CD9 at protein level confirmed the formation of endometrial epithelial-like cells. This culture system may have potential applications in cell therapy and in studies on human embryo implantation.
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Vieira A, Druelle N, Avolio F, Napolitano T, Navarro-Sanz S, Silvano S, Collombat P. β-Cell Replacement Strategies: The Increasing Need for a "β-Cell Dogma". Front Genet 2017. [PMID: 28634486 PMCID: PMC5459879 DOI: 10.3389/fgene.2017.00075] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Type 1 diabetes is an auto-immune disease resulting in the loss of pancreatic β-cells and, consequently, in chronic hyperglycemia. Insulin supplementation allows diabetic patients to control their glycaemia quite efficiently, but treated patients still display an overall shortened life expectancy and an altered quality of life as compared to their healthy counterparts. In this context and due to the ever increasing number of diabetics, establishing alternative therapies has become a crucial research goal. Most current efforts therefore aim at generating fully functional insulin-secreting β-like cells using multiple approaches. In this review, we screened the literature published since 2011 and inventoried the selected markers used to characterize insulin-secreting cells generated by in vitro differentiation of stem/precursor cells or by means of in vivo transdifferentiation. By listing these features, we noted important discrepancies when comparing the different approaches for the initial characterization of insulin-producing cells as true β-cells. Considering the recent advances achieved in this field of research, the necessity to establish strict guidelines has become a subject of crucial importance, especially should one contemplate the next step, which is the transplantation of in vitro or ex vivo generated insulin-secreting cells in type 1 diabetic patients.
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Affiliation(s)
- Andhira Vieira
- Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, iBV, Université Côte d'AzurNice, France
| | - Noémie Druelle
- Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, iBV, Université Côte d'AzurNice, France
| | - Fabio Avolio
- Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, iBV, Université Côte d'AzurNice, France
| | - Tiziana Napolitano
- Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, iBV, Université Côte d'AzurNice, France
| | - Sergi Navarro-Sanz
- Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, iBV, Université Côte d'AzurNice, France
| | - Serena Silvano
- Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, iBV, Université Côte d'AzurNice, France
| | - Patrick Collombat
- Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, iBV, Université Côte d'AzurNice, France
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From Human Mesenchymal Stem Cells to Insulin-Producing Cells: Comparison between Bone Marrow- and Adipose Tissue-Derived Cells. BIOMED RESEARCH INTERNATIONAL 2017; 2017:3854232. [PMID: 28584815 PMCID: PMC5444016 DOI: 10.1155/2017/3854232] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 04/18/2017] [Accepted: 04/23/2017] [Indexed: 12/24/2022]
Abstract
The aim of this study is to compare human bone marrow-derived mesenchymal stem cells (BM-MSCs) and adipose tissue-derived mesenchymal stem cells (AT-MSCs), for their differentiation potentials to form insulin-producing cells. BM-MSCs were obtained during elective orthotopic surgery and AT-MSCs from fatty aspirates during elective cosmetics procedures. Following their expansion, cells were characterized by phenotyping, trilineage differentiation ability, and basal gene expression of pluripotency genes and for their metabolic characteristics. Cells were differentiated according to a Trichostatin-A based protocol. The differentiated cells were evaluated by immunocytochemistry staining for insulin and c-peptide. In addition the expression of relevant pancreatic endocrine genes was determined. The release of insulin and c-peptide in response to a glucose challenge was also quantitated. There were some differences in basal gene expression and metabolic characteristics. After differentiation the proportion of the resulting insulin-producing cells (IPCs), was comparable among both cell sources. Again, there were no differences neither in the levels of gene expression nor in the amounts of insulin and c-peptide release as a function of glucose challenge. The properties, availability, and abundance of AT-MSCs render them well-suited for applications in regenerative medicine. Conclusion. BM-MSCs and AT-MSCs are comparable regarding their differential potential to form IPCs. The availability and properties of AT-MSCs render them well-suited for applications in regenerative medicine.
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Xiang B, Chen L, Wang X, Zhao Y, Wang Y, Xiang C. Transplantation of Menstrual Blood-Derived Mesenchymal Stem Cells Promotes the Repair of LPS-Induced Acute Lung Injury. Int J Mol Sci 2017; 18:ijms18040689. [PMID: 28346367 PMCID: PMC5412275 DOI: 10.3390/ijms18040689] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 03/07/2017] [Accepted: 03/20/2017] [Indexed: 12/12/2022] Open
Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high morbidity and mortality. Menstrual blood-derived stem cells (MenSCs) have been shown to be good therapeutic tools in diseases such as ovarian failure and cardiac fibrosis. However, relevant studies of MenSCs in ALI have not yet proceeded. We hypothesized that MenSC could attenuate the inflammation in lipopolysaccharide (LPS)-induced ALI and promote the repair of damaged lung. ALI model was induced by LPS in C57 mice, and saline or MenSCs were administered via tail vein after four hours. The MenSCs were subsequently detected in the lungs by a live imaging system. The MenSCs not only improved pulmonary microvascular permeability and attenuated histopathological damage, but also mediated the downregulation of IL-1β and the upregulation of IL-10 in bronchoalveolar lavage fluid (BALF) and the damaged lung. Immunohistochemistry revealed the increased expression of proliferating cell nuclear antigen (PCNA) and the reduced expression of caspase-3 indicating the beneficial effect of MenSCs. Keratinocyte growth factor (KGF) was also upregulated after MenSCs administrated. As shown using transwell co-culture, the MenSCs also could improve the viability of BEAS-2B cells and inhibit LPS-induced apoptosis. These findings suggest that MenSC-based therapies could be promising strategies for treating ALI.
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Affiliation(s)
- Bingyu Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310027, China.
| | - Lu Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310027, China.
| | - Xiaojun Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310027, China.
| | - Yongjia Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310027, China.
| | - Yanling Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310027, China.
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310027, China.
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Wang Z, Wang Y, Yang T, Li J, Yang X. Study of the reparative effects of menstrual-derived stem cells on premature ovarian failure in mice. Stem Cell Res Ther 2017; 8:11. [PMID: 28114977 PMCID: PMC5259841 DOI: 10.1186/s13287-016-0458-1] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 11/01/2016] [Accepted: 12/15/2016] [Indexed: 12/18/2022] Open
Abstract
Background Young female patients who receive chemotherapy frequently face premature ovarian failure (POF). The therapeutic potential of stem cells in these patients has been explored in stem cells derived from different sources. However, many of these types of stem cells are either difficult to obtain or obtaining them involves invasive procedures. Here, we show that menstrual-derived stem cells (MenSCs) are easy to access and exhibit mesenchymal stem cell-like properties. MenSCs are therefore a novel source of stem cells that can be used for tissue repair. The aim of this study was to explore the reparative capacity and the mechanism underlying the activities of MenSCs. Methods POF mouse models were established by 7 consecutive days of intraperitoneal injection of cisplatin, and then MenSCs or MenSC-derived conditioned media (CM) were infused via the tail vein. The ovaries were excised after either 7 or 21 days of treatment and the follicles were counted and categorized. Apoptosis of granulosa cells was observed by terminal deoxynucleotidyl transferase mediated dUTP nick end labelling staining. Ovarian function was evaluated by monitoring serum sex hormone levels. Furthermore, MenSC tracking, Q-PCR, and small interfering RNA transfection were used to reveal the inner mechanism of repair. Results MenSC transplantation could improve the ovarian microenvironment by reducing apoptosis in granulosa cells and the fibrosis of ovarian interstitium, which contributes to increase the follicular numbers and return sex hormone levels to normal values. Meanwhile, the transplanted MenSCs directively migrate to ovarian interstitium to play a role in repair rather than differentiate to oocytes directly. Additionally, MenSCs and CM derived from these cells exerted protective effects on damaged ovaries partially by secreting FGF2. Conclusion MenSCs repair ovarian injury, improve ovarian function, and stimulate regeneration, suggesting that transplantation of MenSCs may provide an effective and novel method for treating POF.
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Affiliation(s)
- Zhen Wang
- Department of Gynecology and Obstetrics, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China
| | - Yueling Wang
- Department of Gynecology and Obstetrics, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China
| | - Ting Yang
- Department of Gynecology and Obstetrics, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China
| | - Jing Li
- Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China
| | - Xinyuan Yang
- Department of Gynecology and Obstetrics, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China.
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Chen L, Xiang B, Wang X, Xiang C. Exosomes derived from human menstrual blood-derived stem cells alleviate fulminant hepatic failure. Stem Cell Res Ther 2017; 8:9. [PMID: 28115012 PMCID: PMC5260032 DOI: 10.1186/s13287-016-0453-6] [Citation(s) in RCA: 155] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Revised: 11/28/2016] [Accepted: 12/07/2016] [Indexed: 02/08/2023] Open
Abstract
Background Human menstrual blood-derived stem cells (MenSCs) are a novel source of MSCs that provide the advantage of being easy to collect and isolate. Exosomes contain some mRNAs and adhesion molecules that can potentially impact cellular and animal physiology. This study aimed to investigate the therapeutic potential of MenSC-derived exosomes (MenSC-Ex) on AML12 cells (in vitro) and D-GalN/LPS-induced FHF mice (in vivo). Methods Transmission electron microscopy and Western blot were used to identify MenSC-Ex. Antibody array was used to examine cytokine levels on MenSC-Ex. MenSC-Ex were treated in D-GalN/LPS-induced AML12 in vitro. Cell proliferation and apoptosis were measured. MenSC-Ex were injected into the tail veins of mice 24 h before treatment with D-GalN/LPS. Blood and liver tissues served as physiological and biochemical indexes. The number of liver mononuclear cells (MNCs) and the amount of the active apoptotic protein caspase-3 were determined to elaborate the mechanism of hepatoprotective activity. Results Human menstrual blood-derived stem cell-derived exosomes (MenSC-Ex) are bi-lipid membrane vesicles that have a round, ball-like shape with a diameter of approximately 30–100 nm. Cytokine arrays have shown that MenSC-Ex expressed cytokines, including ICAM-1, angiopoietin-2, Axl, angiogenin, IGFBP-6, osteoprotegerin, IL-6, and IL-8. MenSC-Ex markedly improved liver function, enhanced survival rates, and inhibited liver cell apoptosis at 6 h after transplantation. MenSC-Ex migrated to sites of injury and to AML12 cells (a mouse hepatocyte cell line), respectively. Moreover, MenSC-Ex reduced the number of liver mononuclear cells (MNCs) and the amount of the active apoptotic protein caspase-3 in injured livers. Conclusions In conclusion, our results provide preliminary evidence for the anti-apoptotic capacity of MenSC-Ex in FHF and suggest that MenSC-Ex may be an alternative therapeutic approach to treat FHF. Electronic supplementary material The online version of this article (doi:10.1186/s13287-016-0453-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lu Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Bingyu Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Xiaojun Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
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Abstract
Adult stem cells have a major role in endometrial physiology, remodeling, and repair, but they also have a critical role in the development and progression of endometriosis. Bone marrow-derived stem cells (BMDSCs) engraft eutopic endometrium and endometriotic lesions, showing stromal and epithelial fate. Nevertheless, circulating BMDSCs are in limited supply, and the presence of endometriosis depletes stem cells from the blood circulation, preventing their homing in the uterus. Furthermore, stem cells migrate from endometriotic lesion into the uterus, leading to a dysfunctional endometrium. Stem cell trafficking is a central feature of endometriosis. Understanding molecular mechanisms regulating cell mobility and engraftment in endometriosis may reveal new targets for treatment.
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Affiliation(s)
- Nicola Pluchino
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Hugh S Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
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Xu S, Chan RWS, Ng EHY, Yeung WSB. Spatial and temporal characterization of endometrial mesenchymal stem-like cells activity during the menstrual cycle. Exp Cell Res 2016; 350:184-189. [PMID: 27890645 DOI: 10.1016/j.yexcr.2016.11.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 11/22/2016] [Accepted: 11/23/2016] [Indexed: 11/28/2022]
Abstract
The human endometrium is a highly dynamic tissue with the ability to cyclically regenerate during the reproductive life. Endometrial mesenchymal stem-like cells (eMSCs) located throughout the endometrium have shown to functionally contribute to endometrial regeneration. In this study we examine whether the menstrual cycle stage and the location in the endometrial bilayer (superficial and deep portions of the endometrium) has an effect on stem cell activities of eMSCs (CD140b+CD146+ cells). Here we show the percentage and clonogenic ability of eMSCs were constant in the various stages of the menstrual cycle (menstrual, proliferative and secretory). However, eMSCs from the menstrual endometrium underwent significantly more rounds of self-renewal and enabled a greater total cell output than those from the secretory phase. Significantly more eMSCs were detected in the deeper portion of the endometrium compared to the superficial layer but their clonogenic and self-renewal activities remained similar. Our findings suggest that eMSCs are activated in the menstrual phase for the cyclical regeneration of the endometrium.
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Affiliation(s)
- Shan Xu
- Department of Obstetrics and Gynaecology, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China
| | - Rachel W S Chan
- Department of Obstetrics and Gynaecology, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China; Centre of Reproduction, Development of Growth, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
| | - Ernest H Y Ng
- Department of Obstetrics and Gynaecology, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China; Centre of Reproduction, Development of Growth, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China
| | - William S B Yeung
- Department of Obstetrics and Gynaecology, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China; Centre of Reproduction, Development of Growth, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China
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Lu S, Shi G, Xu X, Wang G, Lan X, Sun P, Li X, Zhang B, Gu X, Ichim TE, Wang H. Human endometrial regenerative cells alleviate carbon tetrachloride-induced acute liver injury in mice. J Transl Med 2016; 14:300. [PMID: 27770815 PMCID: PMC5075169 DOI: 10.1186/s12967-016-1051-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 10/05/2016] [Indexed: 01/08/2023] Open
Abstract
Background The endometrial regenerative cell (ERC) is a novel type of adult mesenchymal stem cell isolated from menstrual blood. Previous studies demonstrated that ERCs possess unique immunoregulatory properties in vitro and in vivo, as well as the ability to differentiate into functional hepatocyte-like cells. For these reasons, the present study was undertaken to explore the effects of ERCs on carbon tetrachloride (CCl4)–induced acute liver injury (ALI). Methods An ALI model in C57BL/6 mice was induced by administration of intraperitoneal injection of CCl4. Transplanted ERCs were intravenously injected (1 million/mouse) into mice 30 min after ALI induction. Liver function, pathological and immunohistological changes, cell tracking, immune cell populations and cytokine profiles were assessed 24 h after the CCl4 induction. Results ERC treatment effectively decreased the CCl4-induced elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and improved hepatic histopathological abnormalities compared to the untreated ALI group. Immunohistochemical staining showed that over-expression of lymphocyte antigen 6 complex, locus G (Ly6G) was markedly inhibited, whereas expression of proliferating cell nuclear antigen (PCNA) was increased after ERC treatment. Furthermore, the frequency of CD4+ and CD8+ T cell populations in the spleen was significantly down-regulated, while the percentage of splenic CD4+CD25+FOXP3+ regulatory T cells (Tregs) was obviously up-regulated after ERC treatment. Moreover, splenic dendritic cells in ERC-treated mice exhibited dramatically decreased MHC-II expression. Cell tracking studies showed that transplanted PKH26-labeled ERCs engrafted to lung, spleen and injured liver. Compared to untreated controls, mice treated with ERCs had lower levels of IL-1β, IL-6, and TNF-α but higher level of IL-10 in both serum and liver. Conclusions Human ERCs protect the liver from acute injury in mice through hepatocyte proliferation promotion, as well as through anti-inflammatory and immunoregulatory effects.
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Affiliation(s)
- Shanzheng Lu
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Ganggang Shi
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Xiaoxi Xu
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Grace Wang
- Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Xu Lan
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Peng Sun
- Department of General Surgery, Affiliated Hospital of Weifang Medical University, Shandong, China
| | - Xiang Li
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Baoren Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Xiangying Gu
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | | | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China. .,Tianjin General Surgery Institute, Tianjin, China.
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de Moraes CN, Maia L, Dias MC, Dell'Aqua CPF, da Mota LSLS, Chapwanya A, Landim-Alvarenga FDC, Oba E. Bovine endometrial cells: a source of mesenchymal stem/progenitor cells. Cell Biol Int 2016; 40:1332-1339. [PMID: 27699929 DOI: 10.1002/cbin.10688] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 09/30/2016] [Indexed: 12/21/2022]
Abstract
Endometrial mesenchymal stem/progenitor cells (eMSCs) are multipotent cells known to modulate the immune system and have clinical application for human and animal health. This makes these bovines cells attractive for dual use as cellular therapy and experimental model. The aim of this study was to isolate, evaluate the differentiation potential, immunophenotypic and immunocytochemistry characteristics, chromosomal stability, cloning efficiency, and cryopreservation response of bovine eMSCs collected in two phases of the estrous cycle. For this, cells were isolated and submitted to differentiation for adipogenic and osteogenic lineage. The cells were then characterized by flow cytometer (FC) (vimentin, CD29, CD44, MHC-II, CD34) and immunocytochemistry (vimentin, pan-cytokeratin, CD44) and submitted to cytogenetic and cloning efficiency assay. The cells were also cryopreserved using two different medium of cryopreservation and analyzed by FC for viability, necrosis, late-apoptosis + necrosis, and initial apoptosis rates before and after cryopreservation. We obtained homogeneous cell populations which have fibroblastic morphology and adherence to plastic. These cells expressed high levels of markers CD29, CD44, and vimentin, low expression levels for CD34 and no MHC-II. The cells were chromosomally stable (2n = 60) with high cloning efficiency and no difference (P > 0.05) between medium of cryopreservation or phase was observed after thawing. We showed the presence and differentiation potential of bovine eMSCs, with chromosomal stability and great response to cryopreservation with both medium, which has implications for build biobanks or development of new therapeutic approaches to combat uterine diseases or to study.
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Affiliation(s)
- Carolina Nogueira de Moraes
- Department of Animal Reproduction and Radiology, São Paulo State University, UNESP, Botucatu, São Paulo, Brazil
| | - Leandro Maia
- Department of Animal Reproduction and Radiology, São Paulo State University, UNESP, Botucatu, São Paulo, Brazil
| | - Marianne Camargos Dias
- Department of Animal Reproduction and Radiology, São Paulo State University, UNESP, Botucatu, São Paulo, Brazil
| | - Camila P Freitas Dell'Aqua
- Department of Animal Reproduction and Radiology, São Paulo State University, UNESP, Botucatu, São Paulo, Brazil
| | | | - Aspinas Chapwanya
- Department of Clinical Sciences, Ross University School of Veterinary Medicine, Basseterre, St Kitts and Nevis
| | | | - Eunice Oba
- Department of Animal Reproduction and Radiology, São Paulo State University, UNESP, Botucatu, São Paulo, Brazil
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