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Zhang WY, Liu SM, Wang HB, Deng CY. Exosomal miR-137-3p targets UBE3C to activate STAT3, promoting migration and differentiation into endometrial epithelial cell of human umbilical cord mesenchymal stem cells under hypoxia. World J Stem Cells 2025; 17:100359. [PMID: 40308888 PMCID: PMC12038465 DOI: 10.4252/wjsc.v17.i4.100359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 11/29/2024] [Accepted: 03/24/2025] [Indexed: 04/23/2025] Open
Abstract
BACKGROUND Thin endometrium, leading cause of recurrent implantation failure and infertility, has been found to respond to exosomes. AIM To investigate the efficacy of exosomes in addressing the issue of thin endometrium. METHODS RNA sequencing and reverse transcription-quantitative polymerase chain reaction were employed to identify differentially expressed microRNAs (miRNAs) in human umbilical cord mesenchymal stem cell (hucMSC) treated with exosomes enriched with endometrial cell-derived components. Additionally, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to highlight significant enrichment in specific biological pathways, molecular functions, and cellular components. Transwell and wound healing assays were performed to assess migratory potential, and western blotting was detected protein level. RESULTS A total of 53 differentially expressed miRNAs were identified in hucMSC treated with exosomes enriched with endometrial cell-derived components, comprising 27 upregulated and 26 downregulated miRNAs, which includes miR-137-3p. Enhanced migratory potential was observed in the Transwell and wound healing assays, and western blotting confirmed the epithelial differentiation of hucMSC and the increased p-signal transducer and activator of transcription 3. These effects were attributed to the upregulation of miR-137-3p. CONCLUSION miR-137-3p in exosomes from hypoxia-affected endometrial epithelial cell stimulates the signal transducer and activator of transcription 3 signaling pathway, enhancing the migration and differentiation of hucMSC into endometrial epithelial cell.
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Affiliation(s)
- Wan-Yu Zhang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Si-Miao Liu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Han-Bi Wang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing 100730, China
| | - Cheng-Yan Deng
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing 100730, China.
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Sanjeev K, Guruprasad M, Vikram R, Priyadarshini S, Mazumder A, Inderchand M. Uterine Biosynthesis through Tissue Engineering: An Overview of Current Methods and Status. Curr Pharm Biotechnol 2025; 26:208-221. [PMID: 39161137 DOI: 10.2174/0113892010316780240807104149] [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: 03/15/2024] [Revised: 07/19/2024] [Accepted: 07/23/2024] [Indexed: 08/21/2024]
Abstract
In the last few decades, the rates of infertility among women have been on the rise, usually due to complications with the uterus and related tissue. A wide variety of reasons can cause uterine factor infertility and can be congenital or a result of disease. Uterine transplantation is currently used as a means to enable women with fertility issues to have a natural birth. However, multiple risk factors are involved in uterine transplantation that threaten the lives of the growing fetus and the mother, as a result of which the procedure is not prominently practiced. Uterine tissue engineering provides a potential solution to infertility through the regeneration of replacement of damaged tissue, thus allowing healing and restoration of reproductive capacity. It involves the use of stem cells from the patient incorporated within biocompatible scaffolds to regenerate the entire tissue. This manuscript discusses the need for uterine tissue engineering, giving an overview of the biological and organic material involved in the process. There are numerous existing animal models in which this procedure has been actualized, and the observations from them have been compiled here. These models are used to develop a further understanding of the integration of engineered tissues and the scope of tissue engineering as a treatment for uterine disorders. Additionally, this paper examines the scope and limitations of the procedure.
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Affiliation(s)
- Krithika Sanjeev
- School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Megaswana Guruprasad
- School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Rachna Vikram
- School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Snigdha Priyadarshini
- School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Adhish Mazumder
- School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Manjubala Inderchand
- School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
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Zhang WY, Wang HB, Deng CY. Effects of miR-214-5p and miR-21-5p in hypoxic endometrial epithelial-cell-derived exosomes on human umbilical cord mesenchymal stem cells. World J Stem Cells 2024; 16:906-925. [DOI: 10.4252/wjsc.v16.i11.906] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 07/24/2024] [Accepted: 10/12/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND Thin endometrium seriously affects endometrial receptivity, resulting in a significant reduction in embryo implantation, and clinical pregnancy and live birth rates, and there is no gold standard for treatment. The main pathophysiological characteristics of thin endometrium are increased uterine arterial blood flow resistance, angiodysplasia, slow growth of the glandular epithelium, and low expression of vascular endothelial growth factor, resulting in endometrial epithelial cell (EEC) hypoxia and endometrial tissue aplasia. Human umbilical cord mesenchymal stem cells (HucMSCs) promote repair and regeneration of damaged endometrium by secreting microRNA (miRNA)-carrying exosomes. However, the initiation mechanism of HucMSCs to repair thin endometrium has not yet been clarified.
AIM To determine the role of hypoxic-EEC-derived exosomes in function of HucMSCs and explore the potential mechanism.
METHODS Exosomes were isolated from normal EECs (EEC-exs) and hypoxia-damaged EECs (EECD-exs), before characterization using Western blotting, nanoparticle-tracking analysis, and transmission electron microscopy. HucMSCs were cocultured with EEC-exs or EECD-exs and differentially expressed miRNAs were determined using sequencing. MiR-21-5p or miR-214-5p inhibitors or miR-21-3p or miR-214-5p mimics were transfected into HucMSCs and treated with a signal transducer and activator of transcription 3 (STAT3) activator or STAT3 inhibitor. HucMSC migration was assessed by Transwell and wound healing assays. Differentiation of HucMSCs into EECs was assessed by detecting markers of stromal lineage (Vimentin and CD13) and epithelial cell lineage (CK19 and CD9) using Western blotting and immunofluorescence. The binding of the miRNAs to potential targets was validated by dual-luciferase reporter assay.
RESULTS MiR-21-5p and miR-214-5p were lowly expressed in EECD-ex-pretreated HucMSCs. MiR-214-5p and miR-21-5p inhibitors facilitated the migratory and differentiative potentials of HucMSCs. MiR-21-5p and miR-214-5p targeted STAT3 and protein inhibitor of activated STAT3, respectively, and negatively regulated phospho-STAT3. MiR-21-5p- and miR-214-5p-inhibitor-induced promotive effects on HucMSC function were reversed by STAT3 inhibition. MiR-21-5p and miR-214-5p overexpression repressed HucMSC migration and differentiation, while STAT3 activation reversed these effects.
CONCLUSION Low expression of miR-21-5p/miR-214-5p in hypoxic-EEC-derived exosomes promotes migration and differentiation of HucMSCs into EECs via STAT3 signaling. Exosomal miR-214-5p/miR-21-5p may function as valuable targets for thin endometrium.
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Affiliation(s)
- Wan-Yu Zhang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Han-Bi Wang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing 100730, China
| | - Cheng-Yan Deng
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing 100730, China
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Sun L, Cheng Y, Wang J, Wu D, Yuan L, Wei X, Li Y, Gao J, Zhang G. Exosomal miR-21-5p derived from endometrial stromal cells promotes angiogenesis by targeting TIMP3 in ovarian endometrial cysts. J Mol Med (Berl) 2024; 102:1327-1342. [PMID: 39227403 DOI: 10.1007/s00109-024-02483-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 08/06/2024] [Accepted: 08/26/2024] [Indexed: 09/05/2024]
Abstract
Endometriosis is a multifactorial gynecological disease, with angiogenesis as a key hallmark. The role of exosomal microRNAs (miRNAs) in endometriosis is not well understood. This study investigates differentially expressed exosomal miRNAs linked to angiogenesis in endometriosis, clarifies their molecular mechanisms, and identifies potential targets. Primary endometrial stromal cells (ESCs) were cultured, and exosomes were extracted. In a co-culture system, ESC-derived exosomes were taken up by human umbilical vein endothelial cells (HUVECs). Endometriosis implant-ESC-derived exosomes (EI-EXOs) significantly promoted HUVEC proliferation, migration and tube formation compared to normal endometrium-exosomes (NE-EXOs), a finding consistent in vivo in mice. MiRNA sequencing and bioinformatics identified differentially expressed miR-21-5p from EI-EXOs, confirmed by RT-qPCR. The miR-21-5p inhibitor or GW4869 attenuated EI-EXO-induced HUVEC proliferation, migration, and tube formation. TIMP3 overexpression diminished the pro-angiogenic effect of EI-EXOs, which was reversed by adding EI-EXOs or upregulating miR-21-5p. These findings validate the crosstalk between ESCs and HUVECs mediated by exosomal miR-21-5p, and confirm the miR-21-5p-TIMP3 axis in promoting angiogenesis in endometriosis. KEY MESSAGES: ESC-derived exosomes were found to be taken up by recipient cells, i.e. HUVECs. Functionally, endometriosis implant-ESC-derived exosomes (EI-EXOs) could significantly promote the proliferation, migration and tube formation of HUVECs compared to normal endometrium-exosomes (NE-EXOs). Through miRNA sequencing and bioinformatics analysis, differentially expressed miR-21-5p released by EI-EXOs was chosen, as confirmed by qRT-PCR. miR-21-5p inhibitor or GW4869 was found to attenuate the proliferation, migration, and tube formation of HUVECs induced by EI-EXOs. In turn, TIMP3 overexpression diminished the pro-angiogenic effect of EI-EXOs, and this angiogenic phenotype was reversed once EI-EXOs were added or miR-21-5p was upregulated.
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Affiliation(s)
- Liyuan Sun
- Department of Gynaecology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
- NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Yan Cheng
- Department of Gynaecology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Jing Wang
- Department of Gynaecology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Di Wu
- Department of Gynaecology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Lin Yuan
- Department of Gynaecology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Xiaoyu Wei
- Department of Gynaecology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Yan Li
- Department of Gynaecology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Jie Gao
- Department of Gynaecology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Guangmei Zhang
- Department of Gynaecology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
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Patel AA, Mohamed AH, Rizaev J, Mallick AK, Qasim MT, Abdulmonem WA, Jamal A, Hattiwale HM, Kamal MA, Ahmad F. Application of mesenchymal stem cells derived from the umbilical cord or Wharton's jelly and their extracellular vesicles in the treatment of various diseases. Tissue Cell 2024; 89:102415. [PMID: 38851032 DOI: 10.1016/j.tice.2024.102415] [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: 02/13/2024] [Revised: 04/26/2024] [Accepted: 05/20/2024] [Indexed: 06/10/2024]
Abstract
Mesenchymal stem cells (MSCs) originating from the umbilical cord (UC) or Wharton's jelly (WJ) have attracted substantial interest due to their potential to augment therapeutic approaches for a wide range of disorders. These cells demonstrate a wide range of capabilities in the process of differentiating into a multitude of cell types. Additionally, they possess a significant capacity for proliferation and are conveniently accessible. Furthermore, they possess a status of being immune-privileged, exhibit minimal tumorigenic characteristics, and raise minimal ethical concerns. Consequently, they are well-suited candidates for tissue regeneration and the treatment of diseases. Additionally, UC-derived MSCs offer a substantial yield compared to other sources. The therapeutic effects of these MSCs are closely associated with the release of nanosized extracellular vesicles (EVs), including exosomes and microvesicles (MVs), containing lipids, microRNAs, and proteins that facilitate intercellular communication. Due to their reduced tumorigenic and immunogenic characteristics, in addition to their convenient manipulability, EVs have arisen as a viable alternative for the management of disorders. The favorable characteristics of UC-MSCs or WJ-MSCs and their EVs have generated significant attention in clinical investigations encompassing diverse pathologies. Therefore, we present a review encompassing current preclinical and clinical investigations, examining the implications of UC-MSCs in diverse diseases, including those affecting bone, cartilage, skin, liver, kidney, neural, lung, cardiovascular, muscle, and retinal tissues, as well as conditions like cancer, diabetes, sepsis, and others.
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Affiliation(s)
- Ayyub Ali Patel
- Clinical Biochemistry Department, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Asma'a H Mohamed
- Biomedical Engineering Department, College of Engineering and Technologies, Al-Mustaqbal University, Hilla, Babil 51001, Iraq.
| | - Jasur Rizaev
- Department of Public Health and Healthcare management, Rector, Samarkand State Medical University, 18, Amir Temur Street, Samarkand, Uzbekistan
| | - Ayaz Khurram Mallick
- Clinical Biochemistry Department, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Maytham T Qasim
- College of Health and Medical Technology, Al-Ayen University, Thi-Qar 64001, Iraq
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Azfar Jamal
- Department of Biology, College of Science Al-Zulfi, Majmaah University, Al-Majmaah 11952, Saudi Arabia; Health and Basic Science Research Centre, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Haroonrashid M Hattiwale
- Department of Basic Medical Sciences, College of Medicine, Majmaah University, Al-Majmaah 11952, Saudi Arabia.
| | - Mohammad Azhar Kamal
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia
| | - Fuzail Ahmad
- College of Applied Sciences, Almaarefa University, Diriya, Riyadh 13713, Saudi Arabia
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Jin B, Ding X, Dai J, Peng C, Zhu C, Wei Q, Chen X, Qiang R, Ding X, Du H, Deng W, Yang X. Deciphering decidual deficiencies in recurrent spontaneous abortion and the therapeutic potential of mesenchymal stem cells at single-cell resolution. Stem Cell Res Ther 2024; 15:228. [PMID: 39075579 PMCID: PMC11287859 DOI: 10.1186/s13287-024-03854-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 07/17/2024] [Indexed: 07/31/2024] Open
Abstract
BACKGROUND Recurrent spontaneous abortion (RSA) is a challenging condition that affects the health of women both physically and mentally, but its pathogenesis and treatment have yet to be studied in detail. In recent years, Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) have been shown to be effective in treating various diseases. Current understanding of RSA treatment using WJ-MSCs is limited, and the exact mechanisms of WJ-MSCs action in RSA remains largely unclear. In this study, we explored the decidual deficiencies in RSA and the therapeutic potential of WJ-MSCs at single-cell resolution. METHODS Three mouse models were established: a normal pregnancy group, an RSA group, and a WJ-MSC treatment group. Decidual tissue samples were collected for single-cell RNA sequencing (scRNA-seq) and functional verification, including single-cell resolution in situ hybridization on tissues (SCRINSHOT) and immunofluorescence. RESULTS We generated a single-cell atlas of decidual tissues from normal pregnant, RSA, and WJ-MSC-treated mice and identified 14 cell clusters in the decidua on day 14. Among these cell populations, stromal cells were the most abundant cell clusters in the decidua, and we further identified three novel subclusters (Str_0, Str_1, and Str_2). We also demonstrated that the IL17 and TNF signaling pathways were enriched for upregulated DEGs of stromal cells in RSA mice. Intriguingly, cell-cell communication analysis revealed that Str_1 cell-related gene expression was greatly reduced in the RSA group and rescued in the WJ-MSC treatment group. Notably, the interaction between NK cells and other cells in the RSA group was attenuated, and the expression of Spp1 (identified as an endometrial toleration-related marker) was significantly reduced in the NK cells of the RSA group but could be restored by WJ-MSC treatment. CONCLUSION Herein, we implemented scRNA-seq to systematically evaluate the cellular heterogeneity and transcriptional regulatory networks associated with RSA and its treatment with WJ-MSCs. These data revealed potential therapeutic targets of WJ-MSCs to remodel the decidual subpopulations in RSA and provided new insights into decidua-derived developmental defects at the maternal-foetal interface.
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Affiliation(s)
- Beibei Jin
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medicine School of Nantong University, Nantong, Jiangsu, China
- Department of Gynecology, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Xiaoying Ding
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medicine School of Nantong University, Nantong, Jiangsu, China
| | - Jiamin Dai
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medicine School of Nantong University, Nantong, Jiangsu, China
| | - Chen Peng
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Chunyu Zhu
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medicine School of Nantong University, Nantong, Jiangsu, China
| | - Qinru Wei
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medicine School of Nantong University, Nantong, Jiangsu, China
| | - Xinyi Chen
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medicine School of Nantong University, Nantong, Jiangsu, China
| | - Ronghui Qiang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medicine School of Nantong University, Nantong, Jiangsu, China
| | - Xiaoyi Ding
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medicine School of Nantong University, Nantong, Jiangsu, China
| | - Hongxiang Du
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medicine School of Nantong University, Nantong, Jiangsu, China
| | - Wenbo Deng
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, School of Medicine, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China.
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, China.
| | - Xiaoqing Yang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
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Dias Da Silva I, Wuidar V, Zielonka M, Pequeux C. Unraveling the Dynamics of Estrogen and Progesterone Signaling in the Endometrium: An Overview. Cells 2024; 13:1236. [PMID: 39120268 PMCID: PMC11312103 DOI: 10.3390/cells13151236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 06/25/2024] [Accepted: 07/19/2024] [Indexed: 08/10/2024] Open
Abstract
The endometrium is crucial for the perpetuation of human species. It is a complex and dynamic tissue lining the inner wall of the uterus, regulated throughout a woman's life based on estrogen and progesterone fluctuations. During each menstrual cycle, this multicellular tissue undergoes cyclical changes, including regeneration, differentiation in order to allow egg implantation and embryo development, or shedding of the functional layer in the absence of pregnancy. The biology of the endometrium relies on paracrine interactions between epithelial and stromal cells involving complex signaling pathways that are modulated by the variations of estrogen and progesterone levels across the menstrual cycle. Understanding the complexity of estrogen and progesterone receptor signaling will help elucidate the mechanisms underlying normal reproductive physiology and provide fundamental knowledge contributing to a better understanding of the consequences of hormonal imbalances on gynecological conditions and tumorigenesis. In this narrative review, we delve into the physiology of the endometrium, encompassing the complex signaling pathways of estrogen and progesterone.
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Grants
- J.0165.24, 7.6529.23, J.0153.22, 7.4580.21F, 7.6518.21, J.0131.19 Fund for Scientific Research
- FSR-F-2023-FM, FSR-F-2022-FM, FSR-F-2021-FM, FSR-F-M-19/6761 University of Liège
- 2020, 2021, 2022 Fondation Léon Fredericq
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Affiliation(s)
| | | | | | - Christel Pequeux
- Tumors and Development, Estrogen-Sensitive Tissues and Cancer Team, GIGA-Cancer, Laboratory of Biology, University of Liège, 4000 Liège, Belgium; (I.D.D.S.); (V.W.); (M.Z.)
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Fan J, Xie J, Liao Y, Lai B, Zhou G, Lian W, Xiong J. Human umbilical cord-derived mesenchymal stem cells and auto-crosslinked hyaluronic acid gel complex for treatment of intrauterine adhesion. Aging (Albany NY) 2024; 16:6273-6289. [PMID: 38568100 PMCID: PMC11042966 DOI: 10.18632/aging.205704] [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: 10/24/2023] [Accepted: 03/09/2024] [Indexed: 04/23/2024]
Abstract
OBJECTIVE The purpose of this study was to explore the therapeutic characteristics of mesenchymal stem cells generated from human umbilical cord (hUC-MSCs) when utilized in conjunction with auto-crosslinked hyaluronic acid gel (HA-gel) for the management of intrauterine adhesion (IUA). The goal was to see how this novel therapy could enhance healing and improve outcomes for IUA patients. METHODS In this study, models of intrauterine adhesion (IUA) were established in Sprague-Dawley (SD) rats, which were then organized and divided into hUC-MSCs groups. The groups involved: hUC-MSCs/HA-gel group, control group, and HA-gel group. Following treatment, the researchers examined the uterine cavities and performed detailed analyses of the endometrial tissues to determine the effectiveness of the interventions. RESULTS The results indicated that in comparison with to the control group, both HA-gel, hUC-MSCs, and hUC-MSCs/HA-gel groups showed partial repair of IUA. However, in a more notable fashion transplantation of hUC-MSCs/HA-gel complex demonstrated significant dual repair effects. Significant outcomes were observed in the group treated with hUC-MSCs and HA-gel, they showed thicker endometrial layers, less fibrotic tissue, and a higher number of endometrial glands. This treatment strategy also resulted in a significant improvement in fertility restoration, indicating a profound therapeutic effect. CONCLUSIONS The findings of this study suggest that both HA-gel, hUC-MSCs, and hUC-MSCs/HA-gel complexes have the potential for partial repair of IUA and fertility restoration caused by endometrium mechanical injury. Nonetheless, the transplantation of the hUC-MSCs/HA-gel complex displayed exceptional dual healing effects, combining effective anti-adhesive properties with endometrial regeneration stimuli.
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Affiliation(s)
- Jiaying Fan
- Department of Obstetrics and Gynaecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Jingying Xie
- Department of Obstetrics and Gynaecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Yunsheng Liao
- Department of Obstetrics and Gynaecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Baoyu Lai
- Department of Obstetrics and Gynaecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Guixin Zhou
- Department of Obstetrics and Gynaecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Wenqin Lian
- Department of Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Jian Xiong
- Department of Obstetrics and Gynaecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
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9
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Wu Y, Gu S, Cobb JM, Dunn GH, Muth TA, Simchick CJ, Li B, Zhang W, Hua X. E2-Loaded Microcapsules and Bone Marrow-Derived Mesenchymal Stem Cells with Injectable Scaffolds for Endometrial Regeneration Application. Tissue Eng Part A 2024; 30:115-130. [PMID: 37930721 DOI: 10.1089/ten.tea.2023.0238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2023] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BMSCs) have been recognized as new candidates for the treatment of serious endometrial injuries. However, owing to the local microenvironment of damaged endometrium, transplantation of BMSCs yielded disappointing results. In this study, Pectin-Pluronic® F-127 hydrogel as scaffolds were fabricated to provide three-dimensional architecture for the attachment, growth, and migration of BMSCs. E2 was encapsulated into the W/O/W microspheres to construct pectin-based E2-loaded microcapsules (E2 MPs), which has the potential to serve as a long-term reliable source of E2 for endometrial regeneration. Then, the BMSCs/E2 MPs/scaffolds system was injected into the uterine cavity of mouse endometrial injury model for treatment. At 4 weeks after transplantation, the system increased proliferative abilities of uterine endometrial cells, facilitated microvasculature regeneration, and restored the ability of endometrium to receive an embryo, suggesting that the BMSCs/E2 MPs/scaffolds system is a promising treatment option for endometrial regeneration. Furthermore, the mechanism of E2 in promoting the repair of endometrial injury was also investigated. Exosomes are critical paracrine mediators that act as biochemical cues to direct stem cell differentiation. In this study, it was found that the expression of endometrial epithelial cell (EEC) markers was upregulated in BMSCs treated by exosomes secreted from endometrial stromal cells (ESCs-Exos). Exosomes derived from E2-stimulated ESCs further promoted the expression level of EECs markers in BMSCs, suggesting exosomes released from ESCs by E2 stimulation could enhance the differentiation efficiency of BMSCs. Therefore, exosomes derived from ESCs play paracrine roles in endometrial regeneration stimulated by E2 and provide optimal estrogenic response.
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Affiliation(s)
- Yuelin Wu
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, Shanghai Tongji University School of Medicine, Shanghai, China
| | - Shengyi Gu
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, Shanghai Tongji University School of Medicine, Shanghai, China
| | - Jonathan M Cobb
- Chemical and Biomolecular Engineering Program, Department of Physics and Chemistry, Milwaukee School of Engineering, Milwaukee, Wisconsin, USA
| | - Griffin H Dunn
- Chemical and Biomolecular Engineering Program, Department of Physics and Chemistry, Milwaukee School of Engineering, Milwaukee, Wisconsin, USA
| | - Taylor A Muth
- Chemical and Biomolecular Engineering Program, Department of Physics and Chemistry, Milwaukee School of Engineering, Milwaukee, Wisconsin, USA
| | - Chloe J Simchick
- Chemical and Biomolecular Engineering Program, Department of Physics and Chemistry, Milwaukee School of Engineering, Milwaukee, Wisconsin, USA
| | - Baoguo Li
- School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Wujie Zhang
- Chemical and Biomolecular Engineering Program, Department of Physics and Chemistry, Milwaukee School of Engineering, Milwaukee, Wisconsin, USA
| | - Xiaolin Hua
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, Shanghai Tongji University School of Medicine, Shanghai, China
- Department of Obstetrics, Shanghai First Maternity and Infant Hospital, Shanghai Tongji University School of Medicine, Shanghai, China
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10
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Kurenkova AD, Presniakova VS, Mosina ZA, Kibirskiy PD, Romanova IA, Tugaeva GK, Kosheleva NV, Vinogradov KS, Kostjuk SV, Kotova SL, Rochev YA, Medvedeva EV, Timashev PS. Resveratrol's Impact on the Chondrogenic Reagents' Effects in Cell Sheet Cultures of Wharton's Jelly-Derived MSCs. Cells 2023; 12:2845. [PMID: 38132166 PMCID: PMC10741663 DOI: 10.3390/cells12242845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 12/08/2023] [Accepted: 12/12/2023] [Indexed: 12/23/2023] Open
Abstract
Human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) are of great interest in tissue engineering. We obtained hWJ-MSCs from four patients, and then we stimulated their chondrogenic phenotype formation in vitro by adding resveratrol (during cell expansion) and a canonical Wnt pathway activator, LiCl, as well as a Rho-associated protein kinase inhibitor, Y27632 (during differentiation). The effects of the added reagents on the formation of hWJ-MSC sheets destined to repair osteochondral injuries were investigated. Three-dimensional hWJ-MSC sheets grown on P(NIPAM-co-NtBA)-based matrices were characterized in vitro and in vivo. The combination of resveratrol and LiCl showed effects on hWJ-MSC sheets similar to those of the basal chondrogenic medium. Adding Y27632 decreased both the proportion of hypertrophied cells and the expression of the hyaline cartilage markers. In vitro, DMSO was observed to impede the effects of the chondrogenic factors. The mouse knee defect model experiment revealed that hWJ-MSC sheets grown with the addition of resveratrol and Y27632 were well integrated with the surrounding tissues; however, after 3 months, the restored tissue was identical to that of the naturally healed cartilage injury. Thus, the combination of chondrogenic supplements may not always have additive effects on the progress of cell culture and could be neutralized by the microenvironment after transplantation.
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Affiliation(s)
- Anastasiia D. Kurenkova
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
| | - Viktoria S. Presniakova
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
| | - Zlata A. Mosina
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
| | - Pavel D. Kibirskiy
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
| | - Irina A. Romanova
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
| | - Gilyana K. Tugaeva
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
| | - Nastasia V. Kosheleva
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
- FSBSI “Institute of General Pathology and Pathophysiology”, Baltiyskaya St. 8, Moscow 125315, Russia
| | - Kirill S. Vinogradov
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
| | - Sergei V. Kostjuk
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
- Department of Chemistry, Belarussian State University, 14 Leningradskaya St., 220006 Minsk, Belarus
- Research Institute for Physical Chemical Problems of the Belarusian State University, 14 Leningradskaya St., 220006 Minsk, Belarus
| | - Svetlana L. Kotova
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
| | - Yury A. Rochev
- Center for Research in Medical Devices (CÚRAM), National University of Ireland Galway, H91 W2TY Galway, Ireland
| | - Ekaterina V. Medvedeva
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
| | - Peter S. Timashev
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow 119991, Russia
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11
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Habib R, Fahim S, Wahid M, Ainuddin J. Optimisation of a Method for the Differentiation of Human Umbilical Cord-derived Mesenchymal Stem Cells Toward Renal Epithelial-like Cells. Altern Lab Anim 2023; 51:363-375. [PMID: 37831588 DOI: 10.1177/02611929231207774] [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] [Indexed: 10/15/2023]
Abstract
Human umbilical cord-derived mesenchymal stem cells (hucMSCs) can differentiate into multiple cell lineages, but few methods have been developed to generate kidney lineage cells. Due to their human origin, pluripotent nature and immunomodulatory properties, these stem cells are attractive candidates for clinical applications such as the repair or regeneration of damaged organs. This study evaluated the renal differentiation potential of hucMSCs, when exposed for 10 days to optimised concentrations of retinoic acid, activin-A and bone morphogenetic protein-7 (BMP-7) in various combinations, with and without the priming of the cells with a Wnt signalling pathway activator (CHIR99021). The hucMSCs were isolated and characterised according to surface marker expression (CD73, CD90, CD44, CD146 and CD8) and tri-lineage differentiation potential. The expression of key marker genes (OSR1, TBXT, HOXA13, SIX2, PAX2, KRT18 and ZO1) was examined by qRT-PCR. Specific marker protein expression (E-cadherin, cytokeratin-8 and cytokeratin-19) was analysed by immunocytochemistry. CHIR99021-primed cells treated with the retinoic acid, activin-A and BMP-7 cocktail showed epithelial cell-like differentiation - i.e. distinct phenotypic changes, as well as upregulated gene and protein expression, were observed that were consistent with an epithelial cell phenotype. Thus, our results showed that hucMSCs can efficiently differentiate into renal epithelial-like cells. This work may help in the development of focused therapeutic strategies, in which lineage-defined human stem cells can be used for renal regeneration.
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Affiliation(s)
- Rakhshinda Habib
- Dow Research Institute of Biotechnology and Biomedical Sciences, Dow University of Health Sciences (Ojha campus), Karachi, Pakistan
| | - Shumaila Fahim
- Dow Research Institute of Biotechnology and Biomedical Sciences, Dow University of Health Sciences (Ojha campus), Karachi, Pakistan
| | - Mohsin Wahid
- Department of Pathology, Dow International Medical College, Dow University of Health Sciences (Ojha campus), Karachi, Pakistan
| | - Jahanara Ainuddin
- Department of Gynaecology and Obstetrics, Dow University Hospital, Karachi, Pakistan
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12
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Stefańska K, Nemcova L, Blatkiewicz M, Pieńkowski W, Ruciński M, Zabel M, Mozdziak P, Podhorska-Okołów M, Dzięgiel P, Kempisty B. Apoptosis Related Human Wharton's Jelly-Derived Stem Cells Differentiation into Osteoblasts, Chondrocytes, Adipocytes and Neural-like Cells-Complete Transcriptomic Assays. Int J Mol Sci 2023; 24:10023. [PMID: 37373173 DOI: 10.3390/ijms241210023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/31/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) exhibit multilineage differentiation potential, adhere to plastic, and express a specific set of surface markers-CD105, CD73, CD90. Although there are relatively well-established differentiation protocols for WJ-MSCs, the exact molecular mechanisms involved in their in vitro long-term culture and differentiation remain to be elucidated. In this study, the cells were isolated from Wharton's jelly of umbilical cords obtained from healthy full-term deliveries, cultivated in vitro, and differentiated towards osteogenic, chondrogenic, adipogenic and neurogenic lineages. RNA samples were isolated after the differentiation regimen and analyzed using an RNA sequencing (RNAseq) assay, which led to the identification of differentially expressed genes belonging to apoptosis-related ontological groups. ZBTB16 and FOXO1 were upregulated in all differentiated groups as compared to controls, while TGFA was downregulated in all groups. In addition, several possible novel marker genes associated with the differentiation of WJ-MSCs were identified (e.g., SEPTIN4, ITPR1, CNR1, BEX2, CD14, EDNRB). The results of this study provide an insight into the molecular mechanisms involved in the long-term culture in vitro and four-lineage differentiation of WJ-MSCs, which is crucial to utilize WJ-MSCs in regenerative medicine.
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Affiliation(s)
- Katarzyna Stefańska
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
- Cellivia 3 S.A., 61-623 Poznan, Poland
| | - Lucie Nemcova
- Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, 27721 Libechov, Czech Republic
| | - Małgorzata Blatkiewicz
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
| | - Wojciech Pieńkowski
- Division of Perinatology and Women's Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Marcin Ruciński
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
| | - Maciej Zabel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Division of Anatomy and Histology, University of Zielona Góra, 65-046 Zielona Góra, Poland
| | - Paul Mozdziak
- Prestage Department of Poultry Sciences, North Carolina State University, Raleigh, NC 27695, USA
| | - Marzenna Podhorska-Okołów
- Division of Ultrastructural Research, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
| | - Piotr Dzięgiel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
- Division of Anatomy, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Department of Obstetrics and Gynecology, University Hospital and Masaryk University, 60177 Brno, Czech Republic
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27695, USA
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13
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Gemayel J, Chaker D, El Hachem G, Mhanna M, Salemeh R, Hanna C, Harb F, Ibrahim A, Chebly A, Khalil C. Mesenchymal stem cells-derived secretome and extracellular vesicles: perspective and challenges in cancer therapy and clinical applications. Clin Transl Oncol 2023:10.1007/s12094-023-03115-7. [PMID: 36808392 DOI: 10.1007/s12094-023-03115-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 02/07/2023] [Indexed: 02/19/2023]
Abstract
Stem cell-based therapies have been foreshowed as a promising therapeutic approach for the treatment of several diseases. However, in the cancer context, results obtained from clinical studies were found to be quite limited. Deeply implicated in inflammatory cues, Mesenchymal, Neural, and Embryonic Stem Cells have mainly been used in clinical trials as a vehicle to deliver and stimulate signals in tumors niche. Although these stem cells have shown some therapeutical promises, they still face several challenges, including their isolation, immunosuppression potential, and tumorigenicity. In addition, regulatory and ethical concerns limit their use in several countries. Mesenchymal stem cells (MSC) have emerged as a gold standard adult stem cell medicine tool due to their distinctive characteristics, such as self-renewal and potency to differentiate into numerous cell types with lower ethical restrictions. Secreted extracellular vesicles (EVs), secretomes, and exosomes play a crucial role in mediating cell-to-cell communication to maintain physiological homeostasis and influence pathogenesis. Due to their low immunogenicity, biodegradability, low toxicity, and ability to transfer bioactive cargoes across biological barriers, EVs and exosomes were considered an alternative to stem cell therapy through their immunological features. MSCs-derived EVs, exosomes, and secretomes showed regenerative, anti-inflammatory, and immunomodulation properties while treating human diseases. In this review, we provide an overview of the paradigm of MSCs derived exosomes, secretome, and EVs cell-free-based therapies, we will focus on MSCs-derived components in anti-cancer treatment with decreased risk of immunogenicity and toxicity. Astute exploration of MSCs may lead to a new opportunity for efficient therapy for patients with cancer.
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Affiliation(s)
- Jack Gemayel
- Faculty of Health Sciences, Balamand University, Beirut, Lebanon
| | - Diana Chaker
- INSERM, National Institute of Health and Medical Research, Paris XI, Paris, France
- Reviva Stem Cell Platform for Research and Applications Center, Bsalim, Lebanon
| | - Georges El Hachem
- Balamand University, Faculty of Medicine, Beirut, Lebanon
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al Kurah, P.O. Box 100, Kalhat, Lebanon
| | - Melissa Mhanna
- Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
| | - Rawad Salemeh
- Reviva Stem Cell Platform for Research and Applications Center, Bsalim, Lebanon
| | - Colette Hanna
- Faculty of Medicine, Lebanese American University Medical Center, Rizk Hospital, Beirut, Lebanon
| | - Frederic Harb
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al Kurah, P.O. Box 100, Kalhat, Lebanon
| | - Ahmad Ibrahim
- Reviva Stem Cell Platform for Research and Applications Center, Bsalim, Lebanon
- Balamand University, Faculty of Medicine, Beirut, Lebanon
| | - Alain Chebly
- Medical Genetics Unit, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
- Higher Institute of Public Health, Saint Joseph University, Beirut, Lebanon
| | - Charbel Khalil
- Reviva Stem Cell Platform for Research and Applications Center, Bsalim, Lebanon.
- Bone Marrow Transplant Unit, Burjeel Medical City, Abu Dhabi, UAE.
- Stem Cell Institute, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon.
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14
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Rodríguez-Eguren A, Gómez-Álvarez M, Francés-Herrero E, Romeu M, Ferrero H, Seli E, Cervelló I. Human Umbilical Cord-Based Therapeutics: Stem Cells and Blood Derivatives for Female Reproductive Medicine. Int J Mol Sci 2022; 23:ijms232415942. [PMID: 36555583 PMCID: PMC9785531 DOI: 10.3390/ijms232415942] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/04/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022] Open
Abstract
There are several conditions that lead to female infertility, where traditional or conventional treatments have limited efficacy. In these challenging scenarios, stem cell (SC) therapies have been investigated as alternative treatment strategies. Human umbilical cord (hUC) mesenchymal stem cells (hUC-MSC), along with their secreted paracrine factors, extracts, and biomolecules, have emerged as promising therapeutic alternatives in regenerative medicine, due to their remarkable potential to promote anti-inflammatory and regenerative processes more efficiently than other autologous treatments. Similarly, hUC blood derivatives, such as platelet-rich plasma (PRP), or isolated plasma elements, such as growth factors, have also demonstrated potential. This literature review aims to summarize the recent therapeutic advances based on hUC-MSCs, hUC blood, and/or other plasma derivatives (e.g., extracellular vesicles, hUC-PRP, and growth factors) in the context of female reproductive medicine. We present an in-depth analysis of the principal molecules mediating tissue regeneration, compiling the application of these therapies in preclinical and clinical studies, within the context of the human reproductive tract. Despite the recent advances in bioengineering strategies that sustain delivery and amplify the scope of the therapeutic benefits, further clinical trials are required prior to the wide implementation of these alternative therapies in reproductive medicine.
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Affiliation(s)
- Adolfo Rodríguez-Eguren
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT 05610, USA
| | | | - Emilio Francés-Herrero
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, 46010 Valencia, Spain
| | - Mónica Romeu
- Gynecological Service, Consortium General University Hospital of Valencia, 46014 Valencia, Spain
| | - Hortensia Ferrero
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
| | - Emre Seli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT 05610, USA
- IVIRMA New Jersey, Basking Ridge, NJ 07920, USA
| | - Irene Cervelló
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
- Correspondence: or
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15
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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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16
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He W, Zhu X, Xin A, Zhang H, Sun Y, Xu H, Li H, Yang T, Zhou D, Yan H, Sun X. Long-term maintenance of human endometrial epithelial stem cells and their therapeutic effects on intrauterine adhesion. Cell Biosci 2022; 12:175. [PMID: 36258228 PMCID: PMC9580151 DOI: 10.1186/s13578-022-00905-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 09/25/2022] [Indexed: 11/05/2022] Open
Abstract
Background The human endometrium is a highly regenerative tissue that is believed to have two main types of stem cells: endometrial mesenchymal/stromal stem cells (eMSCs) and endometrial epithelial stem cells (eESCs). So far, eMSCs have been extensively studied, whereas the studies of eESCs are constrained by the inability to culture and expand them in vitro. The aim of this study is to establish an efficient method for the production of eESCs from human endometrium for potential clinical application in intrauterine adhesion (IUA). Results Here we developed a culture condition with a combination of some small molecules for in vitro culturing and expansion of human SSEA-1+ cells. The SSEA-1+ cells exhibited stem/progenitor cell activity in vitro, including clonogenicity and differentiation capacity into endometrial epithelial cell-like cells. In addition, the SSEA-1+ cells, embedded in extracellular matrix, swiftly self-organized into organoid structures with long-term expansion capacity and histological phenotype of the human endometrial epithelium. Specifically, we found that the SSEA-1+ cells showed stronger therapeutic potential than eMSCs for IUA in vitro. In a rat model of IUA, in situ injection of the SSEA-1+ cells-laden chitosan could efficiently reduce fibrosis and facilitate endometrial regeneration. Conclusions Our work demonstrates an approach for isolation and expansion of human eESCs in vitro, and an appropriate marker, SSEA-1, to identify eESCs. Furthermore, the SSEA-1+ cells-laden chitosan might provide a novel cell-based approach for IUA treatment. These findings will advance the understanding of pathophysiology during endometrial restoration which may ultimately lead to more rational clinical practice. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00905-4.
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Affiliation(s)
- Wen He
- grid.8547.e0000 0001 0125 2443Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Xuejing Zhu
- Shanghai Celliver Biotechnology Co. Ltd, Shanghai, China
| | - Aijie Xin
- grid.8547.e0000 0001 0125 2443NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Fudan University, Shanghai, China
| | - Hongdan Zhang
- Shanghai Celliver Biotechnology Co. Ltd, Shanghai, China
| | - Yiming Sun
- grid.8547.e0000 0001 0125 2443Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Hua Xu
- grid.412312.70000 0004 1755 1415Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - He Li
- grid.412312.70000 0004 1755 1415Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Tianying Yang
- grid.8547.e0000 0001 0125 2443Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Dan Zhou
- grid.8547.e0000 0001 0125 2443Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Hexin Yan
- Shanghai Celliver Biotechnology Co. Ltd, Shanghai, China
| | - Xiaoxi Sun
- grid.8547.e0000 0001 0125 2443Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China ,grid.412312.70000 0004 1755 1415Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China ,grid.412312.70000 0004 1755 1415Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
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17
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Zhou S, Lei Y, Wang P, Chen J, Zeng L, Qu T, Maldonado M, Huang J, Han T, Wen Z, Tian E, Meng X, Zhong Y, Gu J. Human Umbilical Cord Mesenchymal Stem Cells Encapsulated with Pluronic F-127 Enhance the Regeneration and Angiogenesis of Thin Endometrium in Rat via Local IL-1 β Stimulation. Stem Cells Int 2022; 2022:7819234. [PMID: 35761831 PMCID: PMC9233600 DOI: 10.1155/2022/7819234] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 05/19/2022] [Accepted: 05/20/2022] [Indexed: 02/05/2023] Open
Abstract
Thin endometrium (< 7 mm) could cause low clinical pregnancy, reduced live birth, increased spontaneous abortion, and decreased birth weight. However, the treatments for thin endometrium have not been well developed. In this study, we aim to determine the role of Pluronic F-127 (PF-127) encapsulation of human umbilical cord mesenchymal stem cells (hUC-MSCs) in the regeneration of thin endometrium and its underlying mechanism. Thin endometrium rat model was created by infusion of 95% ethanol. Thin endometrium modeled rat uterus were treated with saline, hUC-MSCs, PF-127, or hUC-MSCs plus PF-127 separately. Regenerated rat uterus was measured for gene expression levels of angiogenesis factors and histological morphology. Angiogenesis capacity of interleukin-1 beta (IL-1β)-primed hUC-MSCs was monitored via quantitative polymerase chain reaction (q-PCR), Luminex assay, and tube formation assay. Decreased endometrium thickness and gland number and increased inflammatory factor IL-1β were achieved in the thin endometrium rat model. Embedding of hUC-MSCs with PF-127 could prolong the hUC-MSCs retaining, which could further enhance endometrium thickness and gland number in the thin endometrium rat model via increasing angiogenesis capacity. Conditional medium derived from IL-1β-primed hUC-MSCs increased the concentration of angiogenesis factors (basic fibroblast growth factor (bFGF), vascular endothelial growth factors (VEGF), and hepatocyte growth factor (HGF)). Improvement in the thickness, number of glands, and newly generated blood vessels could be achieved by uterus endometrium treatment with PF-127 and hUC-MSCs transplantation. Local IL-1β stimulation-primed hUC-MSCs promoted the release of angiogenesis factors and may play a vital role on thin endometrium regeneration.
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Affiliation(s)
- Shuling Zhou
- Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, 610066 Sichuan, China
- Department of Pathology and Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Shantou University Medical College, 22 Xinling Road, Shantou, 515041 Guangdong, China
| | - Yu Lei
- Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, 610066 Sichuan, China
- Department of Pathology and Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Shantou University Medical College, 22 Xinling Road, Shantou, 515041 Guangdong, China
| | - Ping Wang
- Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, 610066 Sichuan, China
| | - Jianying Chen
- Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, 610066 Sichuan, China
| | - Liting Zeng
- Department of Pathology and Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Shantou University Medical College, 22 Xinling Road, Shantou, 515041 Guangdong, China
| | - Ting Qu
- Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, 610066 Sichuan, China
| | - Martin Maldonado
- Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, 610066 Sichuan, China
| | - Jihua Huang
- Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, 610066 Sichuan, China
| | - Tingting Han
- Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, 610066 Sichuan, China
| | - Zina Wen
- Department of Andrology, Chengdu Xi'nan Gynecological Hospital, 66 Bisheng Road, Chengdu, 610066 Sichuan, China
| | - Erpo Tian
- Department of Andrology, Chengdu Xi'nan Gynecological Hospital, 66 Bisheng Road, Chengdu, 610066 Sichuan, China
| | - Xiangqian Meng
- Department of Embryology, Chengdu Jinjiang Hospital for Maternal and Child Health Care, 3 San-guantang Road, Chengdu, 610066 Sichuan, China
| | - Ying Zhong
- Department of Embryology, Chengdu Jinjiang Hospital for Maternal and Child Health Care, 3 San-guantang Road, Chengdu, 610066 Sichuan, China
| | - Jiang Gu
- Department of Pathology and Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Shantou University Medical College, 22 Xinling Road, Shantou, 515041 Guangdong, China
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Scrapie-Responsive Gene 1 Promotes Chondrogenic Differentiation of Umbilical Cord Mesenchymal Stem Cells via Wnt5a. Stem Cells Int 2022; 2022:9124277. [PMID: 35126528 PMCID: PMC8813292 DOI: 10.1155/2022/9124277] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 11/25/2021] [Accepted: 12/29/2021] [Indexed: 11/17/2022] Open
Abstract
Objective Repair of cartilage defects, a common condition resulting from many factors, is still a great challenge. Based on their chondrogenic differentiation ability, mesenchymal stem cell- (MSC-) based cartilage regeneration is a promising approach for cartilage defect repair. However, MSC differentiation into chondroblasts or related cell lineages is elaborately controlled by stem cell differentiation stage factors and affected by an array of bioactive elements, which may impede the efficient production of target cells. Thus, identifying a single transcription factor to promote chondrogenic differentiation is critical. Herein, we explored the mechanism by which scrapie-responsive gene 1 (SCRG1), a candidate gene for cartilage regeneration promotion, regulates chondrogenic differentiation of MSCs. Methods Expression of SCRG1 was detected in umbilical cord-derived MSCs (UCMSCs) by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemical analysis during chondrogenic differentiation. The function of SCRG1 in chondrogenic potential was evaluated after gene knockdown or overexpression by lentiviral vectors. Finally, a rabbit cartilage defect model was established to evaluate the effect of SCRG1 on cartilage repair in vivo. Results Expression of SCRG1 was upregulated during in vitro chondrogenic differentiation of UCMSCs. SCRG1 knockdown inhibited chondrogenic differentiation of UCMSCs, while SCRG1 overexpression promoted chondrogenic differentiation of UCMSCs in vitro. In addition, UCMSC overexpressing SCRG1 promoted cartilage repair in vivo. Mechanistically, SCRG1 promoted chondrogenic differentiation via upregulation of Wnt5a expression and subsequent inhibition of β-catenin. Conclusion Our results showed that SCRG1 promotes chondrogenic differentiation of UCMSCs by inhibiting canonical Wnt/β-catenin signaling through Wnt5a. Our findings provide a future target for chondrogenic differentiation and cartilage regeneration.
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Chen T, Xu T, Cheng M, Fang H, Shen X, Tang Z, Zhao J. Human umbilical cord mesenchymal stem cells regulate CD54 and CD105 in vascular endothelial cells and suppress inflammation in Kawasaki disease. Exp Cell Res 2021; 409:112941. [PMID: 34822812 DOI: 10.1016/j.yexcr.2021.112941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 11/15/2021] [Accepted: 11/18/2021] [Indexed: 11/18/2022]
Abstract
OBJECTIVE The objective was to evaluate the expression levels of CD31+CD54+ and CD31+CD105+ endothelial microparticles (EMPs) before and after intravenous immunoglobulin (IVIG) treatment of Kawasaki disease (KD). To explore the role of human umbilical cord mesenchymal stem cells (hucMSCs) in inhibiting endothelial inflammation in KD, the effects of hucMSCs on the expression of CD54 and CD105 in endothelial cells in KD were analyzed in vivo and in vitro. METHODS The concentrations of IL-1β and VEGF in the peripheral blood of KD or healthy children were detected, and the distributions of CD31+CD54+ and CD31+CD105+ EMPs in platelet-poor plasma (PPP) were analyzed by flow cytometry. Human umbilical vein endothelial cells (HUVECs) were first cocultured with the patients' peripheral blood mononuclear cells (PBMCs). Next, HUVECs were cocultured with hucMSCs after stimulation with inactivated serum from patients. Cell proliferation and migration activities were assessed, and the expression of CD54, CD105 and IL-1β was analyzed. In an in vivo study, hucMSCs were transplanted into KD mice. The locations and expression levels of CD54, CD105 and IL-1β in the heart tissues of mice were analyzed. RESULTS The levels of IL-1β and CD31+CD54+ EMPs were significantly higher before IVIG treatment and 2 weeks after treatment in KD patients (P < 0.01). However, the levels of VEGF and CD31+CD105+ EMPs increased significantly in KD only after IVIG treatment (P < 0.01). KD-inactivated serum stimulation combined with cocultivation of PBMCs can activate inflammation in HUVECs, leading to reduced cell proliferation and migration activities. Cocultivation also increased the expression of CD54 and decreased the expression of CD105 (P < 0.001). Cocultivation with hucMSCs can reverse these changes. Additionally, hucMSC transplantation downregulated the expression of IL-1β and CD54 and significantly upregulated the expression of CD105 in KD mice. CONCLUSION The expression levels of CD31+CD54+ and CD31+CD105+ EMPs showed inconsistent changes at different KD statuses, providing potential markers for clinical application. HucMSCs suppress inflammation and regulate the expression levels of CD54 and CD105 in vascular endothelial cells in KD, possibly providing a new basis for stem cell therapy for KD.
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Affiliation(s)
- Tao Chen
- Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China; Research Institute of Comparative Medicine, Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Ting Xu
- Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China; Research Institute of Comparative Medicine, Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Mingye Cheng
- Department of Pediatrics, Zhongda Hospital Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Hao Fang
- Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Xianjuan Shen
- Department of Clinical Laboratory, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Zhiyuan Tang
- Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
| | - Jianmei Zhao
- Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China.
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20
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Making More Womb: Clinical Perspectives Supporting the Development and Utilization of Mesenchymal Stem Cell Therapy for Endometrial Regeneration and Infertility. J Pers Med 2021; 11:jpm11121364. [PMID: 34945836 PMCID: PMC8707522 DOI: 10.3390/jpm11121364] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/02/2021] [Accepted: 12/12/2021] [Indexed: 12/12/2022] Open
Abstract
The uterus is a homeostatic organ, unwavering in the setting of monthly endometrial turnover, placental invasion, and parturition. In response to ovarian steroid hormones, the endometrium autologously prepares for embryo implantation and in its absence will shed and regenerate. Dysfunctional endometrial repair and regeneration may present clinically with infertility and abnormal menses. Asherman's syndrome is characterized by intrauterine adhesions and atrophic endometrium, which often impacts fertility. Clinical management of infertility associated with abnormal endometrium represents a significant challenge. Endometrial mesenchymal stem cells (MSC) occupy a perivascular niche and contain regenerative and immunomodulatory properties. Given these characteristics, mesenchymal stem cells of endometrial and non-endometrial origin (bone marrow, adipose, placental) have been investigated for therapeutic purposes. Local administration of human MSC in animal models of endometrial injury reduces collagen deposition, improves angiogenesis, decreases inflammation, and improves fertility. Small clinical studies of autologous MSC administration in infertile women with Asherman's Syndrome suggested their potential to restore endometrial function as evidenced by increased endometrial thickness, decreased adhesions, and fertility. The objective of this review is to highlight translational and clinical studies investigating the use of MSC for endometrial dysfunction and infertility and to summarize the current state of the art in this promising area.
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21
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Yu J, Zhang W, Huang J, Gou Y, Sun C, Zhang Y, Mao Y, Wu B, Li C, Liu N, Wang T, Huang J, Wang J. Management of intrauterine adhesions using human amniotic mesenchymal stromal cells to promote endometrial regeneration and repair through Notch signalling. J Cell Mol Med 2021; 25:11002-11015. [PMID: 34724320 PMCID: PMC8642679 DOI: 10.1111/jcmm.17023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 12/13/2022] Open
Abstract
Intrauterine adhesions (IUAs) severely hamper women's reproductive functions. Human amniotic mesenchymal stromal cell (hAMSC) transplantation is effective in treating IUAs. Here, we examined the function of Notch signalling in IUA treatment with hAMSC transplantation. Forty-five Sprague-Dawley female rats were randomly divided into the sham operation, IUA, IUA + E2, IUA + hAMSCs and IUA + hAMSCs + E2 groups. After IUA induction in the rats, hAMSCs promoted endometrial regeneration and repair via differentiation into endometrial epithelial cells. In all groups, the expression of key proteins in Notch signalling was detected in the uterus by immunohistochemistry. The results indicated Notch signalling activation in the hAMSCs and hAMSCs + E2 groups. We could also induce hAMSC differentiation to generate endometrial epithelial cells in vitro. Furthermore, the inhibition of Notch signalling using the AdR-dnNotch1 vector suppressed hAMSC differentiation (assessed by epithelial and mesenchymal marker levels), whereas its activation using the AdR-Jagged1 vector increased differentiation. The above findings indicate Notch signalling mediates the differentiation of hAMSCs into endometrial epithelial cells, thus promoting endometrial regeneration and repair; Notch signalling could have an important function in IUA treatment.
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Affiliation(s)
- Jie Yu
- Department of Obstetrics and Gynecology, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Wenwen Zhang
- Department of Obstetrics and Gynecology, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Jiayue Huang
- Department of Obstetrics and Gynecology, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Yating Gou
- Department of Obstetrics and Gynecology, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Congcong Sun
- Department of Obstetrics and Gynecology, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Yingfeng Zhang
- Department of Obstetrics and Gynecology, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Yanhua Mao
- Department of Obstetrics and Gynecology, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Benyuan Wu
- Department of Obstetrics and Gynecology, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Changjiang Li
- Department of Obstetrics and Gynecology, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Nizhou Liu
- Department of Obstetrics and Gynecology, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Tingting Wang
- Department of Obstetrics and Gynecology, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Jiren Huang
- Department of Obstetrics and Gynecology, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Jia Wang
- Department of Obstetrics and Gynecology, University-Town Hospital of Chongqing Medical University, Chongqing, China
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22
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Ray SK, Mukherjee S. Clinical Practice of Umbilical Cord Blood Stem Cells in Transplantation and Regenerative Medicine - Prodigious Promise for Imminent Times. Recent Pat Biotechnol 2021; 16:16-34. [PMID: 34702158 DOI: 10.2174/1872208315666211026103227] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/22/2021] [Accepted: 09/08/2021] [Indexed: 11/22/2022]
Abstract
The umbilical cord blood is usually disposed of as an unwanted material after parturition; however, today, it is viewed as a regenerative medication so as to create the organ tissues. This cord blood gathered from the umbilical cord is made up of mesenchymal stem cells, hematopoietic stem cells, and multipotent non-hematopoietic stem cells having many therapeutic effects as these stem cells are utilized to treat malignancies, hematological ailments, inborn metabolic problem, and immune deficiencies. Presently, numerous clinical applications for human umbilical cord blood inferred stem cells, as stem cell treatment initiate new research. These cells are showing such a boon to stem cell treatment; it is nevertheless characteristic that the prospect of conservation of umbilical cord blood is gaining impetus. Current research works have demonstrated that about 80 diseases, including cancer, can be treated or relieved utilizing umbilical cord blood stem cells, and every year, many transplants have been effectively done around the world. However, in terms of factors, including patient selection, cell preparation, dosing, and delivery process, the treatment procedure for therapy with minimally manipulated stem cells can be patented. It is also worth thinking about how this patent could affect cord blood banks. Meanwhile, the utilization of cord blood cells is controversial and adult-derived cells may not be as successful, so numerous clinicians have begun working with stem cells that are acquired from umbilical cord blood. This review epitomizes a change in outlook from what has been completed with umbilical cord blood cell research and cord blood banking on the grounds that cord blood cells do not require much in the method of handling for cryopreservation or for transplantation in regenerative medicine.
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Affiliation(s)
| | - Sukhes Mukherjee
- Department of Biochemistry. All India Institute of Medical Sciences. Bhopal, Madhya Pradesh-462020. 0
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23
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Wang S, Shi C, Cai X, Wang Y, Chen X, Han H, Shen H. Human Acellular Amniotic Matrix with Previously Seeded Umbilical Cord Mesenchymal Stem Cells Restores Endometrial Function in a Rat Model of Injury. Mediators Inflamm 2021; 2021:5573594. [PMID: 34531703 PMCID: PMC8438588 DOI: 10.1155/2021/5573594] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 06/24/2021] [Accepted: 08/03/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Abnormal endometrial repair after injury results in the formation of intrauterine adhesions (IUA) and a thin endometrium, which are key causes for implantation failure and infertility. Stem cell transplantation offers a potential alternative for some cases of severe Asherman's syndrome that cannot be treated with surgery or hormonal therapy. Umbilical cord-derived mesenchymal stem cells (UCMSCs) have been reported to repair the damaged endometrium. However, there is no report on the effects of UCMSCs previously seeded on human acellular amniotic matrix (AAM) on endometrial injury. METHODS Absolute ethanol was injected into rat uteri to damage the endometrium. UCMSCs previously seeded on AAM were surgically transplanted. Using a variety of methods, the treatment response was assessed by endometrial thickness, endometrial biomarker expression, endometrial receptivity, cell proliferation, and inflammatory factors. RESULTS Endometrial thickness was markedly improved after UCMSC-AAM transplantation. The expression of endometrial biomarkers, namely, vimentin, cytokeratin, and integrin β3, in treated rats increased compared with untreated rats. In the UCMSC-AAM group, the VEGF expression decreased, whereas that of MMP9 increased compared with the injury group. Moreover, in the AAM group, the MMP9 expression increased. The expression of proinflammatory factors (IL-2, TNFα, and IFN-γ) in the UCMSC-AAM group decreased compared with the untreated group, whereas the expression of anti-inflammatory factors (IL-4, IL-10) increased significantly. CONCLUSIONS UCMSC transplantation using AAM as the carrier can be applied to treat endometrial injury in rats. The successful preparation of lyophilized AAM provides the possibility of secondary infectious disease screening and amniotic matrix quality detection, followed by retrospective analysis. The UCMSC-AAM complex may promote the better application of UCMSCs on the treatment of injured endometrium.
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Affiliation(s)
- Shan Wang
- Peking University People's Hospital, Reproductive Medicine Center, Beijing 100044, China
- Beijing Friendship Hospital, Capital Medical University, Department of Obstetrics and Gynecology, Beijing 100050, China
| | - Cheng Shi
- Peking University People's Hospital, Reproductive Medicine Center, Beijing 100044, China
| | - Xiaohui Cai
- Beijing Friendship Hospital, Capital Medical University, Department of Obstetrics and Gynecology, Beijing 100050, China
| | - Yanbin Wang
- Peking University People's Hospital, Reproductive Medicine Center, Beijing 100044, China
| | - Xi Chen
- Peking University People's Hospital, Reproductive Medicine Center, Beijing 100044, China
| | - Hongjing Han
- Peking University People's Hospital, Reproductive Medicine Center, Beijing 100044, China
| | - Huan Shen
- Peking University People's Hospital, Reproductive Medicine Center, Beijing 100044, China
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24
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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: 35] [Impact Index Per Article: 8.8] [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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25
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Rahmani-Moghadam E, Zarrin V, Mahmoodzadeh A, Owrang M, Talaei-Khozani T. Comparison of the Characteristics of Breast Milk-derived Stem Cells with the Stem Cells Derived from the Other Sources: A Comparative Review. Curr Stem Cell Res Ther 2021; 17:71-90. [PMID: 34161214 DOI: 10.2174/1574888x16666210622125309] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/14/2021] [Accepted: 03/28/2021] [Indexed: 11/22/2022]
Abstract
Breast milk (BrM) not only supplies nutrition, but it also contains a diverse population of cells. It has been estimated that up to 6% of the cells in human milk possess the characteristics of mesenchymal stem cells (MSC). Available data also indicate that these cells are multipotent and capable of self-renewal and differentiation with other cells. In this review, we have compared different characteristics, such as CD markers, differentiation capacity, and morphology of stem cells, derived from human breast milk (hBr-MSC) with human bone marrow (hBMSC), Wharton's jelly (WJMSC), and human adipose tissue (hADMSC). Through the literature review, it was revealed that human breast milk-derived stem cells specifically express a group of cell surface markers, including CD14, CD31, CD45, and CD86. Importantly, a group of markers, CD13, CD29, CD44, CD105, CD106, CD146, and CD166, were identified, which were common in the four sources of stem cells. WJMSC, hBMSC, hADMSC, and hBr-MSC are potently able to differentiate into the mesoderm, ectoderm, and endoderm cell lineages. The ability of hBr-MSCs todifferentiate into the neural stem cells, neurons, adipocyte, hepatocyte, chondrocyte, osteocyte, and cardiomyocytes has made these cells a promising source of stem cells in regenerative medicine, while isolation of stem cells from the commonly used sources, such as bone marrow, requires invasive procedures. Although autologous breast milk-derived stem cells are an accessible source for women who are in the lactation period, breast milk can be considered as a source of stem cells with high differentiation potential without any ethical concern.
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Affiliation(s)
- Ebrahim Rahmani-Moghadam
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vahideh Zarrin
- Laboratory for Stem Cell Research, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Mahmoodzadeh
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Marzieh Owrang
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Talaei-Khozani
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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26
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Jiang X, Li X, Fei X, Shen J, Chen J, Guo M, Li Y. Endometrial membrane organoids from human embryonic stem cell combined with the 3D Matrigel for endometrium regeneration in asherman syndrome. Bioact Mater 2021; 6:3935-3946. [PMID: 33937593 PMCID: PMC8079828 DOI: 10.1016/j.bioactmat.2021.04.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 03/29/2021] [Accepted: 04/04/2021] [Indexed: 12/18/2022] Open
Abstract
Asherman's syndrome (AS), a leading cause of uterine infertility worldwide, is characterized by scarring of the uterine surfaces lacking endometrial epithelial cells, which prevents endometrial regeneration. Current research on cell therapy for AS focuses on mesenchymal and adult stem cells from the endometrium. However, insufficient number, lack of purity, and rapid senescence of endometrial epithelial progenitor cells (EEPCs) during experimental processes restrict their use in cell therapies. In this study, we induced human embryonic stem cells-9 (H9-ESC) into EEPCs by optimizing the induction factors from the definitive endoderm. EEPCs, which act as endometrial epithelial cells, accompanied by human endometrial stromal cells provide a niche environment for the development of endometrial membrane organoids (EMOs) in an in vitro 3D culture model. To investigate the function of EMOs, we transplanted tissue-engineered constructs with EMOs into an in vivo rat AS model. The implantation of EMOs into the damaged endometrium facilitates endometrial regeneration and angiogenesis. Implanting EMOs developed from human embryonic stem cells into the endometrium might prove useful for "endometrial re-engineering" in the treatment of Asherman's syndrome.
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Affiliation(s)
- Xiuxiu Jiang
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310006, China
| | - Xingmiao Li
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310006, China
| | - Xiangwei Fei
- Key Laboratory of Women′s Reproductive Health Research of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310006, China
| | - Jiajie Shen
- Key Laboratory of Women′s Reproductive Health Research of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310006, China
| | - Jianhua Chen
- Department of Pathology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310006, China
| | - Meijun Guo
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310006, China
| | - Yangyang Li
- Key Laboratory of Women′s Reproductive Health Research of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310006, China
- Corresponding author.
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27
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Li Y, Zhang S, Li W, Zheng X, Xue Y, Hu K, Zhou H. Substance P-induced RAD16-I scaffold mediated hUCMSCs stereo-culture triggers production of mineralized nodules and collagen-like fibers by promoting osteogenic genes expression. Am J Transl Res 2021; 13:1990-2005. [PMID: 34017371 PMCID: PMC8129421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 05/05/2020] [Indexed: 06/12/2023]
Abstract
Tissue engineering has become an important therapeutic method for injuries. This study aimed to generate collagen-like matrix constructed by hUCMSCs combining self-assembled polypeptide and evaluate differentiated capacity, safety and biocompatibility. Human umbilical cord tissues were isolated and used to primarily culture hUCMSCs. hUCMSCs were identified using immunofluorescence and flow cytometry. Adipogenic- and osteogenic-differentiation of hUCMSCs were evaluated using Oil-red O and Alizarin-Red staining. Self-assembling collagen peptide RAD16-I hydrogel and substance P (SP) were prepared and combined together to form RAD16-I/SP complex. Surface morphology and ultrastructures were observed with scanning electron microscopic (SEM). hUCMSCs in simulated collagen-like matrix environment were plane-cultured and stereo-cultured. Cell viability was examined using CCK-8 and fluorescent staining assay. Osteogenic genes were detected with qRT-PCR and western blot assay. HE staining and Masson staining were used to assess production of mineralized nodules and collagen-like fibers, respectively. Collagen-like matrix complex by combining RAD16-I/SP complex with stereo-cultured hUCMSCs was successfully generated. hUCMSCs in collagen-like matrix complex demonstrated adipogenic-differentiation and osteogenic-differentiation potential. SP-induced RAD16-I mediated stereo-culture of hUCMSCs demonstrated higher cell activity and proliferation potential. SP-induced RAD16-I mediated stereo-culture of hUCMSCs promoted osteogenesis-related molecules expression. SP-induced RAD16-I mediated stereo-culture of hUCMSCs promoted production of mineralized nodules and triggered formation of collagen-like fibers. Cell-collagen-like matrix complex injection (RAD16-I/SP/hUCMSCs complex) exhibited better biocompatibility and no cytotoxicity. In conclusion, SP-induced RAD16-I mediated stereo-culture of hUCMSCs remarkably promoted osteogenesis-related gene expression, triggered production of mineralized nodules and formation of collagen-like fibers. This established cell-collagen-like matrix complex (RAD16-I/SP/hUCMSCs) injection exhibited better biocompatibility, without cytotoxicity.
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Affiliation(s)
- Yuan Li
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University Xi'an 710032, PR China
| | - Shuyin Zhang
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University Xi'an 710032, PR China
| | - Wantao Li
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University Xi'an 710032, PR China
| | - Xueni Zheng
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University Xi'an 710032, PR China
| | - Yang Xue
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University Xi'an 710032, PR China
| | - Kaijin Hu
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University Xi'an 710032, PR China
| | - Hongzhi Zhou
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University Xi'an 710032, PR China
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Hashemi SS, Mohammadi AA, Moshirabadi K, Zardosht M. Effect of dermal fibroblasts and mesenchymal stem cells seeded on an amniotic membrane scaffold in skin regeneration: A case series. J Cosmet Dermatol 2021; 20:4040-4047. [PMID: 33656768 DOI: 10.1111/jocd.14043] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/25/2021] [Accepted: 02/15/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND Skin wound healing has always been a challenging subject as it involves the coordinated functioning of various cells and molecules. Any disorder in wound healing can cause healing failure and result in chronic wounds. In this study, we hypothesized that co-cultured dermal fibroblasts (DFs) and Wharton's jelly mesenchymal stem cells (WJ-MSCs) seeded on an acellular amniotic membrane scaffold could be used to promote skin regeneration in chronic ulcers. MATERIALS AND METHODS In this case series, the chronic wounds of five diabetic patients aged between 30 and 60 years were treated with co-cultured WJ-MSCs and DFs seeded on an acellular amniotic membrane. Treatment was applied and the wound healing process was evaluated every three days for nine days, with the patients being subsequently followed up for one month. The wound healing percentage, time taken for the wound to heal, and wound size were monitored. RESULTS The mean wound healing rate (WHR) increased progressively in all lesions. The mean percentage of wound healing after transplantation of the biological scaffold enriched with WJ-MSCs and autologous DFs after treatment was 93.92%, respectively. The healing percentage significantly increased after three days; significant decreases in wound size and healing time were recorded after six and nine days of treatment, respectively (p < 0.002); and total skin regeneration and re-epithelialization were achieved by the ninth day of treatment. There were no side effects or complications. CONCLUSION Given the current problems and complications presented by chronic wounds, Novel Clinical approaches involving cell therapy and tissue engineering can be regarded as an attractive therapeutic option for the treatment of chronic and difficult-to-heal wounds.
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Affiliation(s)
- Seyedeh-Sara Hashemi
- Burn and Wound Healing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Akbar Mohammadi
- Burn and Wound Healing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Division of Plastic and Reconstructive Surgery, Department of Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kasra Moshirabadi
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mitra Zardosht
- Burn and Wound Healing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Human Umbilical Cord: Information Mine in Sex-Specific Medicine. Life (Basel) 2021; 11:life11010052. [PMID: 33451112 PMCID: PMC7828611 DOI: 10.3390/life11010052] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 01/08/2021] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Biological differences between sexes should be considered in all stages of research, as sexual dimorphism starts in utero leading to sex-specific fetal programming. In numerous biomedical fields, there is still a lack of stratification by sex despite primary cultured cells retaining memory of the sex and of the donor. The sex of donors in biological research must be known because variations in cells and cellular components can be used as endpoints, biomarkers and/or targets of pharmacological studies. This selective review focuses on the current findings regarding sex differences observed in the umbilical cord, a widely used source of research samples, both in the blood and in the circulating cells, as well as in the different cellular models obtainable from it. Moreover, an overview on sex differences in fetal programming is reported. As it emerges that the sex variable is still often forgotten in experimental models, we suggest that it should be mandatory to adopt sex-oriented research, because only awareness of these issues can lead to innovative research.
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Shi Q, Sun B, Wang D, Zhu Y, Zhao X, Yang X, Zhang Y. Circ6401, a novel circular RNA, is implicated in repair of the damaged endometrium by Wharton's jelly-derived mesenchymal stem cells through regulation of the miR-29b-1-5p/RAP1B axis. Stem Cell Res Ther 2020; 11:520. [PMID: 33261656 PMCID: PMC7708228 DOI: 10.1186/s13287-020-02027-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 11/13/2020] [Indexed: 02/08/2023] Open
Abstract
Background Accumulating evidence indicates that mesenchymal stem cells (MSCs) exert tissue repair effects and therapeutic angiogenesis through their noncoding RNAs (ncRNAs). Our previous studies showed that MSCs derived from Wharton’s jelly (WJ-MSCs) can ameliorate damaged human endometrium by promoting angiogenesis. There is limited information on the functions and mechanism of ncRNAs in MSC-induced endometrial repair, and additional studies are needed for more insights. Methods Here, WJ-MSCs were cocultured with or without endometrial stromal cells (ESCs) damaged by mifepristone (cocultured group versus non-cocultured group). TUNEL staining assays, EdU proliferation assays, flow cytometry apoptosis assays, and western blot assays were performed to observe the reparative effect of WJ-MSCs on damaged ESCs. Subsequently, circular RNA (circRNA) and microRNA microarrays were performed between the two groups. A subset of top upregulated circRNAs was validated by qRT-PCR. The functions of circ6401 (hsa_circ_0006401) in WJ-MSCs were investigated using lentivirus-mediated circRNA overexpression assays. The subcellular localization of circ6401 and miR-29b-1-5p in WJ-MSCs was identified by double RNA fluorescence in situ hybridization. Dual-luciferase reporter assays and western blot assays were performed to elucidate the regulatory mechanisms among circ6401, miR-29b-1-5p, and RAP1B. Results WJ-MSCs significantly improved ESC proliferation and upregulated the expression of vascular angiogenesis markers. Circ6401 was upregulated in WJ-MSCs cocultured with damaged ESCs, while miR-29b-1-5p was significantly downregulated. Furthermore, circ6401 was found to bind to miR-29b-1-5p and prevent it from decreasing the level of RAP1B, a crucial protein involved in the VEGF signaling pathway, which promoted angiogenesis and stimulated the proliferation of ESCs. Conclusions Our results showed the abundance and regulation profiles of ncRNAs of WJ-MSCs during repair of damaged ESCs and, for the first time, clarified the underlying mechanism by which circ6401 promotes endometrial repair by WJ-MSCs; thus, demonstrating that circ6401 may serve as a potential therapeutic target.
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Affiliation(s)
- Qin Shi
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, 19 Xisi Road, Nantong, Jiangsu, 226000, People's Republic of China
| | - Baolan Sun
- Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, People's Republic of China
| | - Di Wang
- Center for Reproductive Medicine, Affiliated Hospital of Nantong University, Nantong, People's Republic of China
| | - Yi Zhu
- Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong, People's Republic of China
| | - Xinxin Zhao
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, 19 Xisi Road, Nantong, Jiangsu, 226000, People's Republic of China
| | - Xiaoqing Yang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, 19 Xisi Road, Nantong, Jiangsu, 226000, People's Republic of China.
| | - Yuquan Zhang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, 19 Xisi Road, Nantong, Jiangsu, 226000, People's Republic of China.
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Esfandyari S, Chugh RM, Park HS, Hobeika E, Ulin M, Al-Hendy A. Mesenchymal Stem Cells as a Bio Organ for Treatment of Female Infertility. Cells 2020; 9:E2253. [PMID: 33050021 PMCID: PMC7599919 DOI: 10.3390/cells9102253] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/01/2020] [Accepted: 10/03/2020] [Indexed: 12/14/2022] Open
Abstract
Female infertility is a global medical condition that can be caused by various disorders of the reproductive system, including premature ovarian failure (POF), polycystic ovary syndrome (PCOS), endometriosis, Asherman syndrome, and preeclampsia. It affects the quality of life of both patients and couples. Mesenchymal stem cells (MSCs) have received increasing attention as a potential cell-based therapy, with several advantages over other cell sources, including greater abundance, fewer ethical considerations, and high capacity for self-renewal and differentiation. Clinical researchers have examined the therapeutic use of MSCs in female infertility. In this review, we discuss recent studies on the use of MSCs in various reproductive disorders that lead to infertility. We also describe the role of microRNAs (miRNAs) and exosomal miRNAs in controlling MSC gene expression and driving MSC therapeutic outcomes. The clinical application of MSCs holds great promise for the treatment of infertility or ovarian insufficiency, and to improve reproductive health for a significant number of women worldwide.
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Affiliation(s)
- Sahar Esfandyari
- Department of Surgery, University of Illinois at Chicago, 820 South Wood Street, Chicago, IL 60612, USA; (S.E.); (R.M.C.); (H.-s.P.); (M.U.)
| | - Rishi Man Chugh
- Department of Surgery, University of Illinois at Chicago, 820 South Wood Street, Chicago, IL 60612, USA; (S.E.); (R.M.C.); (H.-s.P.); (M.U.)
| | - Hang-soo Park
- Department of Surgery, University of Illinois at Chicago, 820 South Wood Street, Chicago, IL 60612, USA; (S.E.); (R.M.C.); (H.-s.P.); (M.U.)
| | - Elie Hobeika
- Fertility Centers of Illinois, Glenview, IL 60026, USA;
| | - Mara Ulin
- Department of Surgery, University of Illinois at Chicago, 820 South Wood Street, Chicago, IL 60612, USA; (S.E.); (R.M.C.); (H.-s.P.); (M.U.)
| | - Ayman Al-Hendy
- Department of Surgery, University of Illinois at Chicago, 820 South Wood Street, Chicago, IL 60612, USA; (S.E.); (R.M.C.); (H.-s.P.); (M.U.)
- Department of Obstetrics and Gynecology, University of Chicago, 5841 South Maryland Ave, Chicago, IL 60637, USA
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Hung HS, Yu AYH, Hsieh SC, Kung ML, Huang HY, Fu RH, Yeh CA, Hsu SH. Enhanced Biocompatibility and Differentiation Capacity of Mesenchymal Stem Cells on Poly(dimethylsiloxane) by Topographically Patterned Dopamine. ACS APPLIED MATERIALS & INTERFACES 2020; 12:44393-44406. [PMID: 32697572 DOI: 10.1021/acsami.0c05747] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Controlling the behavior of mesenchymal stem cells (MSCs) through topographic patterns is an effective approach for stem cell studies. We, herein, reported a facile method to create a dopamine (DA) pattern on poly(dimethylsiloxane) (PDMS). The topography of micropatterned DA was produced on PDMS after plasma treatment. The grid-topographic-patterned surface of PDMS-DA (PDMS-DA-P) was measured for adhesion force and Young's modulus by atomic force microscopy. The surface of PDMS-DA-P demonstrated less stiff and more elastic characteristics compared to either nonpatterned PDMS-DA or PDMS. The PDMS-DA-P evidently enhanced the differentiation of MSCs into various tissue cells, including nerve, vessel, bone, and fat. We further designed comprehensive experiments to investigate adhesion, proliferation, and differentiation of MSCs in response to PDMS-DA-P and showed that the DA-patterned surface had good biocompatibility and did not activate macrophages or platelets in vitro and had low foreign body reaction in vivo. Besides, it protected MSCs from apoptosis as well as excessive reactive oxygen species (ROS) generation. Particularly, the patterned surface enhanced the differentiation capacity of MSCs toward neural and endothelial cells. The stromal cell-derived factor-1α/CXantiCR4 pathway may be involved in mediating the self-recruitment and promoting the differentiation of MSCs. These findings support the potential application of PDMS-DA-P in either cell treatment or tissue repair.
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Affiliation(s)
- Huey-Shan Hung
- Graduate Institute of Biomedical Science, China Medical University, Taichung 40402, Taiwan, R.O.C
- Translational Medicine Research, China Medical University Hospital, Taichung 40402, Taiwan, R.O.C
| | - Alex Yang-Hao Yu
- Ministry of Health & Welfare, Changhua Hospital, Changhua 51341, Taiwan, R.O.C
| | - Shu-Chen Hsieh
- Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan, R.O.C
| | - Mei-Lang Kung
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan, R.O.C
| | - Hsiu-Yuan Huang
- Department of Cosmeceutics and Graduate Institute of Cosmeceutics, China Medical University, Taichung 40402, Taiwan, R.O.C
| | - Ru-Huei Fu
- Graduate Institute of Biomedical Science, China Medical University, Taichung 40402, Taiwan, R.O.C
- Translational Medicine Research, China Medical University Hospital, Taichung 40402, Taiwan, R.O.C
| | - Chun-An Yeh
- Graduate Institute of Biomedical Science, China Medical University, Taichung 40402, Taiwan, R.O.C
| | - Shan-Hui Hsu
- Institute of Polymer Science and Engineering, National Taiwan University, Taipei 10617, Taiwan, R.O.C
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Afflerbach AK, Kiri MD, Detinis T, Maoz BM. Mesenchymal Stem Cells as a Promising Cell Source for Integration in Novel In Vitro Models. Biomolecules 2020; 10:E1306. [PMID: 32927777 PMCID: PMC7565384 DOI: 10.3390/biom10091306] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/02/2020] [Accepted: 09/03/2020] [Indexed: 02/07/2023] Open
Abstract
The human-relevance of an in vitro model is dependent on two main factors-(i) an appropriate human cell source and (ii) a modeling platform that recapitulates human in vivo conditions. Recent years have brought substantial advancements in both these aspects. In particular, mesenchymal stem cells (MSCs) have emerged as a promising cell source, as these cells can differentiate into multiple cell types, yet do not raise the ethical and practical concerns associated with other types of stem cells. In turn, advanced bioengineered in vitro models such as microfluidics, Organs-on-a-Chip, scaffolds, bioprinting and organoids are bringing researchers ever closer to mimicking complex in vivo environments, thereby overcoming some of the limitations of traditional 2D cell cultures. This review covers each of these advancements separately and discusses how the integration of MSCs into novel in vitro platforms may contribute enormously to clinical and fundamental research.
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Affiliation(s)
- Ann-Kristin Afflerbach
- Department of Biomedical Engineering, Tel Aviv University, Tel Aviv 6997801, Israel; (A.-K.A.); (M.D.K.); (T.D.)
- Faculty of Biosciences, Universität Heidelberg, 69120 Heidelberg, Germany
| | - Mark D. Kiri
- Department of Biomedical Engineering, Tel Aviv University, Tel Aviv 6997801, Israel; (A.-K.A.); (M.D.K.); (T.D.)
| | - Tahir Detinis
- Department of Biomedical Engineering, Tel Aviv University, Tel Aviv 6997801, Israel; (A.-K.A.); (M.D.K.); (T.D.)
| | - Ben M. Maoz
- Department of Biomedical Engineering, Tel Aviv University, Tel Aviv 6997801, Israel; (A.-K.A.); (M.D.K.); (T.D.)
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel
- The Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 6997801, Israel
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Yotsumoto F, Iwaguro H, Harada Y, Sobajima S, Suwabe T, Miyamoto S. Adipose tissue-derived regenerative cells improve implantation of fertilized eggs in thin endometrium. Regen Med 2020; 15:1891-1904. [DOI: 10.2217/rme-2020-0037] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aim: Embryo implantation and subsequent pregnancy depends on endometrial thickness. To investigate potential fertility strategies for women with thin endometrium, we explored the efficacy of adipose tissue-derived regenerative cells (ADRCs) on thin endometrium and embryo implantation in a mouse model. Materials & methods: ADRCs isolated from mouse subcutaneous fat were characterized by flow cytometry. Endometrium thickness, endometrial fibrosis, embryo implantation and angiogenesis factors were evaluated in uterine cavities of ethanol-induced thin endometrium mice with ADRC transplantation. Results: ADRCs included adipose-derived stem cells and some blood vessel component cells. ADRCs improved endometrial thickness, endometrial fibrosis and embryo implantation and augmented vascular endothelial growth factor expression in the mouse uterine. Conclusion: ADRCs may be a useful therapeutic strategy to improve fertility of women with thin endometrium.
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Affiliation(s)
- Fusanori Yotsumoto
- Department of Obstetrics & Gynecology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Hideki Iwaguro
- Department of Obstetrics & Gynecology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- SOBAJIMA Clinic, Osaka, Japan
| | | | | | - Takako Suwabe
- Department of Obstetrics & Gynecology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Shingo Miyamoto
- Department of Obstetrics & Gynecology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
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An update on stem cell therapy for Asherman syndrome. J Assist Reprod Genet 2020; 37:1511-1529. [PMID: 32445154 DOI: 10.1007/s10815-020-01801-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 04/28/2020] [Indexed: 02/06/2023] Open
Abstract
The current treatment for Asherman syndrome is limited and not very effective. The aim of this review is to summarize the most recent evidence for stem cells in the treatment of Asherman syndrome. The advent of stem cell therapy has propagated experimentation on mice and humans as a novel treatment. The consensus is that the regenerative capacity of stem cells has demonstrated improved outcomes in terms of fertility and fibrosis in both mice and humans with Asherman syndrome. Stem cells have effects on tissue repair by homing to the injured site, recruiting other cells by secreting chemokines, modulating the immune system, differentiating into other types of cells, proliferating into daughter cells, and potentially having antimicrobial activity. The studies reviewed examine different origins and administration modalities of stem cells. In preclinical models, therapeutic systemic injection of stem cells is more effective than direct intrauterine injection in regenerating the endometrium. In conjunction, bone marrow-derived stem cells have a stronger effect on uterine regeneration than uterine-derived stem cells, likely due to their broader differentiation potency. Clinical trials have demonstrated the initial safety and effectiveness profiles of menstrual, bone marrow, umbilical cord, and adipose tissue-derived stem cells in resumption of menstruation, fertility outcomes, and endometrial regeneration.
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36
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Lv CX, Duan H, Wang S, Gan L, Xu Q. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Promote Proliferation of Allogeneic Endometrial Stromal Cells. Reprod Sci 2020; 27:1372-1381. [PMID: 32006246 DOI: 10.1007/s43032-020-00165-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 12/01/2019] [Indexed: 12/13/2022]
Abstract
Umbilical cord mesenchymal stem cells (UCMSCs) have been proposed as an ideal source for cell-based therapy to promote endometrial repair and regeneration. Furthermore, increasing evidence has indicated that UCMSC-derived exosomes (UCMSC-exos) act as important paracrine mediators to recapitulate the features of MSCs and may play a vital role in this process. UCMSCs and human endometrial stromal cells (ESCs) were isolated and characterized. ESCs were cocultured with UCMSCs and further assessed by flow cytometry and EdU incorporation assays. UCMSC-exos were extracted by differential ultracentrifugation and identified by western blots, transmission electron microscopy, and nanoparticle tracking analysis. The internalization of UCMSC-exos by ESCs was observed under a confocal microscope. ESCs were treated with UCMSC-exos at different concentrations and for different durations, with cell viability evaluated by CCK-8 assays. The cell cycle analysis showed that the percentage of ESCs in S phase significantly increased after coculture with UCMSCs, whereas it significantly decreased after inhibition of UCMSC-exo secretions. EdU incorporation assays also showed a similar trend. The isolated UCMSC-exos had a typical cup-shaped morphology with a monolayer membrane, expressed the specific exosomal markers Alix, CD63, and TSG101 and were approximately 60 to 200 nm in diameter. The PKH26-labeled UCMSC-exos were incorporated into ESCs. Moreover, UCMSC-exos enhanced the cell growth and viability of ESCs in a dose-dependent manner, and the effects occurred in a short period of time. UCMSC-exos promote the proliferation of ESCs in a dose-dependent manner; thus, they could be used as a potential treatment to promote endometrial repair.
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Affiliation(s)
- Cheng-Xiao Lv
- Department of Minimally Invasive Gynecologic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Hua Duan
- Department of Minimally Invasive Gynecologic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People's Republic of China.
| | - Sha Wang
- Department of Minimally Invasive Gynecologic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Lu Gan
- Department of Minimally Invasive Gynecologic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Qian Xu
- Department of Minimally Invasive Gynecologic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People's Republic of China
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37
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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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Khalil C, Moussa M, Azar A, Tawk J, Habbouche J, Salameh R, Ibrahim A, Alaaeddine N. Anti-proliferative effects of mesenchymal stem cells (MSCs) derived from multiple sources on ovarian cancer cell lines: an in-vitro experimental study. J Ovarian Res 2019; 12:70. [PMID: 31351482 PMCID: PMC6660927 DOI: 10.1186/s13048-019-0546-9] [Citation(s) in RCA: 37] [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] [Received: 06/06/2019] [Accepted: 07/18/2019] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have surfaced as ideal candidates for treatment of different therapeutically challenging diseases however their effect on cancer cells is not well determined. In this study, we investigated the effect of MSCs derived from human bone marrow (BM), adipose tissue (AT), and umbilical cord derived MSCs (UC-MSCs) on ovarian cancer.Measurements of ovarian tumor marker proteins were computed by ELISA. Proliferative, apoptosis and anti-inflammatory effects of the MSCs were measured by Flow cytometry (FCM). MMPs expression was measured by RT-PCR.The co-culture of cancer cell lines OVCAR3, CAOV3, IGROV3 and SKOV3 with the conditioned media of MSCs (CM-MSC) and MSCs showed an increase in cellular apoptosis, along with a reduction in the level of CA-125 and a decline of LDH and beta-hCG. A decrease in CD24 of the cancer cell lines in co-culture with the CM-MSCs showed a reduction of the cancer tumorigenicity. In addition, the invasion and aggressiveness of cancer cell lines was significantly decreased by CM-MSC; this was translated by a decrease in MMP-2, MMP-9, and CA-125 mRNA expression, and an increase in TIMP 1, 2, and 3 mRNA expression. An increase in IL-4 and IL-10 cytokines, and a decrease in GM-CSF, IL-6, and IL-9, were also noted.In conclusion, mesenchymal stem cells derived from different sources and their conditioned media appear to have a major role in inhibition of cancer aggressiveness and might be considered as a potential therapeutic tool in ovarian cancer.
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Affiliation(s)
- C Khalil
- Regenerative Medicine and Inflammation Laboratory, Faculty of Medicine, Saint-Joseph University, Beirut, Lebanon
- Reviva Research and Application Center-Lebanese University, Middle East Institute of Health University Hospital, Beirut, Lebanon
| | - M Moussa
- Regenerative Medicine and Inflammation Laboratory, Faculty of Medicine, Saint-Joseph University, Beirut, Lebanon
| | - A Azar
- Reviva Research and Application Center-Lebanese University, Middle East Institute of Health University Hospital, Beirut, Lebanon
| | - J Tawk
- Regenerative Medicine and Inflammation Laboratory, Faculty of Medicine, Saint-Joseph University, Beirut, Lebanon
| | - J Habbouche
- Reviva Research and Application Center-Lebanese University, Middle East Institute of Health University Hospital, Beirut, Lebanon
| | - R Salameh
- Reviva Research and Application Center-Lebanese University, Middle East Institute of Health University Hospital, Beirut, Lebanon
| | - A Ibrahim
- Reviva Research and Application Center-Lebanese University, Middle East Institute of Health University Hospital, Beirut, Lebanon
- Faculty of Medicine, Lebanese University, Beirut, Lebanon
| | - N Alaaeddine
- Regenerative Medicine and Inflammation Laboratory, Faculty of Medicine, Saint-Joseph University, Beirut, Lebanon.
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon.
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Xiao B, Yang W, Lei D, Huang J, Yin Y, Zhu Y, You Z, Wang F, Sun S. PGS Scaffolds Promote the In Vivo Survival and Directional Differentiation of Bone Marrow Mesenchymal Stem Cells Restoring the Morphology and Function of Wounded Rat Uterus. Adv Healthc Mater 2019; 8:e1801455. [PMID: 30734535 DOI: 10.1002/adhm.201801455] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 12/26/2018] [Indexed: 01/23/2023]
Abstract
Intrauterine adhesion (IUA) causing infertility and recurrent miscarriage of reproductive female mammals usually results from endometrium injury. Nevertheless, there is no efficient therapeutic method to avoid IUA. Bone marrow derived mesenchymal stem cells (BMSCs) are an important cell source for tissue regeneration. This study designs and explores the ability of BMSC-loaded elastic poly(glycerol sebacate) (PGS) scaffold to prevent IUA and compares the effect of PGS with poly(lactic-co-glycolic acid) (PLGA) and collagen scaffolds in resumption of damaged rat uteruses. The 3D architecture provided by PGS scaffolds favors the attachment and growth of rat BMSCs. In vivo bioluminescence imaging shows that compared with direct BMSC intrauterine injection, PLGA, and collagen scaffolds, the PGS scaffold significantly prolongs the retention time of BMSCs in a wounded rat uterus model. More importantly, BMSCs can directly differentiate into endometrial stromal cells after transplantation of PGS/BMSCs constructs, but not PLGA/BMSCs and collagen/BMSCs. It is found that the level of transforming growth factor β1 (TGF-β1), basic fibroblast growth factor (bFGF), vascular endothelial growth factor, and insulin-like growth factors in the injured endometrium adjacent to PGS/BMSCs constructs is higher than those of rats receiving PLGA/BMSCs, collagen/BMSCs, or BMSCs intrauterine transplantation. Besides, transplantation of PGS/BMSCs leads to better morphology recovery of the damaged uterus than PLGA/BMSCs and collagen/BMSCs. The receptive fertility of PGS/BMSCs is 72.2 ± 6.4%, similar to the one of collagen/BMSCs, but significantly higher than 42.3 ± 3.9% in PLGA/BMSCs. Taken together, PGS/BMSCs may be a promising candidate for preventing IUA.
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Affiliation(s)
- Bang Xiao
- Department of Medical Genetics; Second Military Medical University; 800 Xiangyin Road Shanghai 200433 P. R. China
| | - Wenjun Yang
- Department of Medical Genetics; Second Military Medical University; 800 Xiangyin Road Shanghai 200433 P. R. China
| | - Dong Lei
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials; International Joint Laboratory for Advanced Fiber and Low-dimension Materials; College of Materials Science and Engineering; Donghua University; Shanghai 201620 P. R. China
| | - Jinfeng Huang
- Department of Medical Genetics; Second Military Medical University; 800 Xiangyin Road Shanghai 200433 P. R. China
| | - Yupeng Yin
- Department of Medical Genetics; Second Military Medical University; 800 Xiangyin Road Shanghai 200433 P. R. China
| | - Yiqing Zhu
- Department of Medical Genetics; Second Military Medical University; 800 Xiangyin Road Shanghai 200433 P. R. China
| | - Zhengwei You
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials; International Joint Laboratory for Advanced Fiber and Low-dimension Materials; College of Materials Science and Engineering; Donghua University; Shanghai 201620 P. R. China
| | - Fang Wang
- Department of Medical Genetics; Second Military Medical University; 800 Xiangyin Road Shanghai 200433 P. R. China
| | - Shuhan Sun
- Department of Medical Genetics; Second Military Medical University; 800 Xiangyin Road Shanghai 200433 P. R. China
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Sun B, Shi L, Shi Q, Jiang Y, Su Z, Yang X, Zhang Y. Circular RNAs are abundantly expressed and upregulated during repair of the damaged endometrium by Wharton's jelly-derived mesenchymal stem cells. Stem Cell Res Ther 2018; 9:314. [PMID: 30442201 PMCID: PMC6238312 DOI: 10.1186/s13287-018-1046-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 10/10/2018] [Accepted: 10/14/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) exhibit strong and powerful potential in repairing different diseases. The expression profile of circular RNA (circRNA) provides valuable insight for regulation of the repair process and exploration of reparative effect mechanisms. METHODS Human endometrial stromal cells (ESCs) were cultured with mifepristone to obtain damaged ESCs, which were then cocultured with or without WJ-MSCs (cocultured group versus non-cocultured group) to observe the reparative effect upon damaged ESCs by WJ-MSCs. CircRNA microarray was performed between the two groups. Based on the transcriptomics data, the differential gene expression profiles of the two groups were analyzed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and network analysis methods. Screening of a circRNA database was performed, and the results were confirmed by quantitative polymerase chain reaction (qPCR). RESULTS WJ-MSCs exerted a reparative effect upon damaged ESCs in the cocultured group such as improved cell morphology, higher proliferative ability, and lower apoptosis rate. CircRNA array showed that 7757 circRNAs were differentially expressed in ESCs from the cocultured group. Mitotic cell cycle, cell cycle process, and nuclear division ranked top in the GO upregulated list of the two groups, while DNA replication and cell cycle ranked top in the KEGG pathway analysis upregulated list of the two groups. The nine most aberrantly expressed circRNAs were selected for further verification in the same cohort of samples by microarray analysis. Seven of the nine most aberrantly circRNAs were confirmed to be significantly upregulated in the cocultured group. And four of the seven circRNAs (hsa_circ_0015825, hsa-circRNA4049-38, hsa-circRNA5028-15, and hsa_circ_0111659) expression both in ESCs and WJ-MSCs tended to decrease with time by qPCR. The levels of the remaining three circRNAs (hsa-circRNA8881-21, hsa_circ_0020492 and hsa_circ_ 0026141) did not change significantly over time in either ESCs or WJ-MSCs. Moreover, we focused on hsa_circRNA_0111659 and predicted its miRNAs and targeted mRNA. The association of circRNA-miRNA-mRNA is likely to be involved in regulating the repair of endometrial damage. CONCLUSIONS Our results presented the abundant and upregulated circRNAs profile during repair of the damaged endometrium by WJ-MSCs and provided a novel perspective for circRNAs in the regulation of WJ-MSCs for endometrial repair.
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Affiliation(s)
- Baolan Sun
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, People's Republic of China
| | - Lei Shi
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, People's Republic of China
| | - Qin Shi
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, People's Republic of China
| | - Yao Jiang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Soochow, People's Republic of China
| | - Zhangyao Su
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University School of Medicine, 19 Xishi Road, Nantong, 226006, Jiangsu, People's Republic of China
| | - Xiaoqing Yang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, People's Republic of China.
| | - Yuquan Zhang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, People's Republic of China.
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