scholarly journals iPSC-Derived Ovarian Tissue Restores Ovarian Function in Subfertile Mice and After Gonadotoxic Chemotherapy

2019 ◽  
Author(s):  
K.M. Elias ◽  
N.W. Ng ◽  
K.U. Dam ◽  
A. Milne ◽  
E.R. Disler ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Nude Mice ◽  
Ovarian Tissue ◽  
Stem Cell Differentiation ◽  
Reproductive Hormones ◽  
Reproductive Age ◽  
Premature Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Hormone Synthesis

AbstractMany reproductive age women with cancer who receive chemotherapy are exposed to gonadotoxic agents and risk diminished ovarian reserve, sterility, and premature menopause. Previously, we reported the derivation of steroidogenic ovarian cells from induced pluripotent and embryonic stem cells. Derived cells not only produced reproductive hormones, but also displayed markers of ovarian tissue and primordial gametes. Here, we describe that human follicular fluid (HFF), when added to our stem cell differentiation system, enhances the steroidogenic potential of differentiating stem cells and increases the subpopulation of cells that express the ovarian and germ cell markers GJA1 and ZP1, respectively. More importantly, using an in vivo model of chemotherapy-induced premature ovarian insufficiency in subfertile nude mice, we demonstrate that orthotopic implantation of these derived cells restores ovarian hormone synthesis and produces functional stem cell-derived oocytes. Additionally, these cells also ameliorate subfertility in nude mice, as demonstrated by the delivery of multiple litters of healthy pups from stem cell-derived oocytes. Collectively, these data support the hypothesis that stem cell-derived steroidogenic ovarian tissue could be used to promote neo-gametogenesis and treat the endocrinologic and reproductive sequelae of premature ovarian insufficiency.One Sentence SummaryWe show that orthotopic injection of sorted, differentiated iPSCs in ovaries of subfertile mice restores reproductive hormone synthesis and fertility.

scholarly journals Human umbilical cord mesenchymal stem cells restore the ovarian metabolome and rescue premature ovarian insufficiency in mice

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yan Zhao ◽  
Jiao Ma ◽  
Peiye Yi ◽  
Jun Wu ◽  
Feiyan Zhao ◽  
...  
Keyword(s):  
Amino Acids ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Umbilical Cord ◽  
Ovarian Function ◽  
Premature Ovarian Insufficiency ◽  
Reproductive Capacity ◽  
Human Umbilical Cord ◽  
Ovarian Insufficiency

Abstract Background Premature ovarian insufficiency (POI) is an ovarian dysfunction that seriously affects a woman’s physiological health and reproduction. Mesenchymal stem cell (MSC) transplantation offers a promising treatment option for ovarian restoration in rodent POI models. However, the efficacy and mechanism of it remain unclear. Methods POI mice model was generated by cyclophosphamide and busulfan, followed with the treatment of tail-vein injection of the human umbilical cord mesenchymal stem cells (hUCMSCs). Maternal physiological changes and offspring behavior were detected. To reveal the pathogenesis and therapeutic mechanisms of POI, we first compared the metabolite profiles of healthy and POI ovarian tissues using untargeted metabolomics analyses. After stem cell therapy, we then collected the ovaries from control, POI, and hUCMSC-treated POI groups for lipid metabolomics and pseudotargeted metabolomics analysis. Results Our results revealed remarkable changes of multiple metabolites, especially lipids, in ovarian tissues after POI generation. Following the transplantation of clinical-grade hUCMSCs, POI mice exhibited significant improvements in body weight, sex hormone levels, estrous cycles, and reproductive capacity. Lipid metabolomics and pseudotargeted metabolomics analyses for the ovaries showed that the metabolite levels in the POI group, mainly lipids, glycerophospholipids, steroids, and amino acids changed significantly compared with the controls’, and most of them returned to near-healthy levels after receiving hUCMSC treatment. Meanwhile, we also observed an increase of monosaccharide levels in the ovaries from POI mice and a decrease after stem cell treatment. Conclusions hUCMSCs restore ovarian function through activating the PI3K pathway by promoting the level of free amino acids, consequently improving lipid metabolism and reducing the concentration of monosaccharides. These findings provide potential targets for the clinical diagnosis and treatment of POI.

scholarly journals Induction a Rat Model of Premature Ovarian Insufficiency (POI) Using D Galactose Feeding During the Critical Periods of Development: an Experimental Protocol

2020 ◽  
Author(s):  
Marzieh Roatami Dovom ◽  
Mahsa Noroozzadeh ◽  
Nariman Mosaffa ◽  
Abbas Piryaei ◽  
Azita Zadevakili ◽  
...  
Keyword(s):  
Rat Model ◽  
Clinical Manifestations ◽  
Female Offspring ◽  
Reproductive Hormones ◽  
Reproductive Age ◽  
Premature Ovarian Insufficiency ◽  
Control Group ◽  
Critical Periods ◽  
Ovarian Insufficiency ◽  
The Third

Abstract Introduction: Premature ovarian insufficiency (POI) affects about 1% of women of reproductive age, with no curative treatment. Several efforts have been made to develop an animal model of POI that mimics all manifestations of this disease; however, these models are limited due to increased mortality or high toxicity. Overall, well-developed animal models may improve our knowledge of diseases and can be suitable for identifying the underlying mechanisms and detecting the optimal treatment methods. In the present study, we aimed to present a functional rat model of POI, mimicking the clinical manifestations of POI in women. Materials and Methods: This experimental study was performed in two steps. In the first step (induction of the rat POI model), a total of 40 pregnant Wistar rats were randomly divided into four groups. Three experimental groups were fed galactose-enriched diets at days 3-15 of pregnancy (group 1); on the third day of pregnancy until the end of pregnancy (group 2); and on the third day of pregnancy until the end of the weaning period (group 3). Also, group 4 (control group) was fed a standard pellet during pregnancy and breastfeeding period. In the second step of the study, the ovarian morphology (microscopic and macroscopic), reproductive hormones, and immunological and metabolic characteristics of the female offspring were examined in all experimental groups and compared with the controls at three time points, that is, postnatal days (PNDs) 45, 105, and 180 of age.Results: In this study, we presented an optimal model of POI that highly mimics the clinical manifestations of this disease in women. Conclusion: A functional rat model of POI may be suitable for increasing our understanding of this disease and filling the knowledge gaps.

scholarly journals DYRK1A Negatively Regulates CDK5-SOX2 Pathway and Self-Renewal of Glioblastoma Stem Cells

2021 ◽  
Vol 22 (8) ◽  
pp. 4011
Author(s):  
Brianna Chen ◽  
Dylan McCuaig-Walton ◽  
Sean Tan ◽  
Andrew P. Montgomery ◽  
Bryan W. Day ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Critical Role ◽  
Stem Cell Differentiation ◽  
Neural Progenitor Cell ◽  
Cellular Heterogeneity ◽  
Differentiation Potential ◽  
Glioblastoma Stem Cells ◽  
Glioblastoma Stem Cell

Glioblastoma display vast cellular heterogeneity, with glioblastoma stem cells (GSCs) at the apex. The critical role of GSCs in tumour growth and resistance to therapy highlights the need to delineate mechanisms that control stemness and differentiation potential of GSC. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) regulates neural progenitor cell differentiation, but its role in cancer stem cell differentiation is largely unknown. Herein, we demonstrate that DYRK1A kinase is crucial for the differentiation commitment of glioblastoma stem cells. DYRK1A inhibition insulates the self-renewing population of GSCs from potent differentiation-inducing signals. Mechanistically, we show that DYRK1A promotes differentiation and limits stemness acquisition via deactivation of CDK5, an unconventional kinase recently described as an oncogene. DYRK1A-dependent inactivation of CDK5 results in decreased expression of the stemness gene SOX2 and promotes the commitment of GSC to differentiate. Our investigations of the novel DYRK1A-CDK5-SOX2 pathway provide further insights into the mechanisms underlying glioblastoma stem cell maintenance.

scholarly journals Nuclear Export of Smads by RanBP3L Regulates Bone Morphogenetic Protein Signaling and Mesenchymal Stem Cell Differentiation

2015 ◽  
Vol 35 (10) ◽  
pp. 1700-1711 ◽  
Author(s):  
Fenfang Chen ◽  
Xia Lin ◽  
Pinglong Xu ◽  
Zhengmao Zhang ◽  
Yanzhen Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Mesenchymal Stem Cell ◽  
Nuclear Export ◽  
Stem Cell Differentiation ◽  
Bmp Signaling ◽  
Dependent Manner ◽  
Mesenchymal Stem Cell Differentiation

Bone morphogenetic proteins (BMPs) play vital roles in regulating stem cell maintenance and differentiation. BMPs can induce osteogenesis and inhibit myogenesis of mesenchymal stem cells. Canonical BMP signaling is stringently controlled through reversible phosphorylation and nucleocytoplasmic shuttling of Smad1, Smad5, and Smad8 (Smad1/5/8). However, how the nuclear export of Smad1/5/8 is regulated remains unclear. Here we report that the Ran-binding protein RanBP3L acts as a nuclear export factor for Smad1/5/8. RanBP3L directly recognizes dephosphorylated Smad1/5/8 and mediates their nuclear export in a Ran-dependent manner. Increased expression of RanBP3L blocks BMP-induced osteogenesis of mouse bone marrow-derived mesenchymal stem cells and promotes myogenic induction of C2C12 mouse myoblasts, whereas depletion of RanBP3L expression enhances BMP-dependent stem cell differentiation activity and transcriptional responses. In conclusion, our results demonstrate that RanBP3L, as a nuclear exporter for BMP-specific Smads, plays a critical role in terminating BMP signaling and regulating mesenchymal stem cell differentiation.

Magnetic field assisted stem cell differentiation – role of substrate magnetization in osteogenesis

2015 ◽  
Vol 3 (16) ◽  
pp. 3150-3168 ◽  
Author(s):  
Sunil Kumar Boda ◽  
Greeshma Thrivikraman ◽  
Bikramjit Basu
Keyword(s):  
Magnetic Field ◽  
Tissue Engineering ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Bone Tissue Engineering ◽  
Human Mesenchymal Stem Cells ◽  
Stem Cell Differentiation

Substrate magnetization as a tool for modulating the osteogenesis of human mesenchymal stem cells for bone tissue engineering applications.

scholarly journals Induction of Cancerous Stem Cells during Embryonic Stem Cell Differentiation

2012 ◽  
Vol 287 (44) ◽  
pp. 36777-36791 ◽  
Author(s):  
Hiroaki Fujimori ◽  
Mima Shikanai ◽  
Hirobumi Teraoka ◽  
Mitsuko Masutani ◽  
Ken-ichi Yoshioka
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation

Biomaterials Nano Geometry for Control of Stem Cell Differentiation

2009 ◽  
Vol 1239 ◽  
Author(s):  
Karla Brammer ◽  
Seunghan Oh ◽  
Sungho Jin
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Stem Cell Differentiation ◽  
Human Mesenchymal Stem Cell ◽  
Oxide Surface ◽  
Specific Cell ◽  
Implant Surface ◽  
Multipotent Stem Cells

AbstractTwo important goals in stem cell research are to control the cell proliferation without differentiation, and also to direct the differentiation into a specific cell lineage when desired. Recent studies indicate that the nanostructures substantially influence the stem cell behavior. It is well known that mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate into stromal lineages such as adipocyte, chondrocyte, fibroblast, myocyte, and osteoblast cell types. By examining the cellular behavior of MSCs cultured in vitro on nanostructures, some understanding of the effects that the nanostructures have on the stem cell’s response has been obtained. Here we demonstrate that TiO2 nanotubes produced by anodization on Ti implant surface can regulate human mesenchymal stem cell (hMSC) differentiation towards an osteoblast lineage in the absence of osteogenic inducing factors. Altering the dimensions of nanotubular-shaped titanium oxide surface structures independently allowed either augmented human mesenchymal stem cell (hMSC) adhesion at smaller diameter levels or a specific differentiation of hMSCs into osteoblasts using only the geometric cues. Small (˜30 nm diameter) nanotubes promoted adhesion without noticeable differentiation, while larger (˜70 - 100 nm diameter) nanotubes elicited a dramatic, ˜10 fold stem cell elongation, which induced cytoskeletal stress and selective differentiation into osteoblast-like cells, offering a promising nanotechnology-based route for novel orthopaedics-related hMSC treatments. The fact that a guided and preferential osteogenic differentiation of stem cells can be achieved using substrate nanotopography alone without using potentially toxic, differentiation-inducing chemical agents is significant, which can be useful for future development of novel and enhanced stem cell control and therapeutic implant development.

scholarly journals Comparison of the Proliferation and Differentiation Potential of Human Urine-, Placenta Decidua Basalis-, and Bone Marrow-Derived Stem Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Chengguang Wu ◽  
Long Chen ◽  
Yi-zhou Huang ◽  
Yongcan Huang ◽  
Ornella Parolini ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Stem Cell Differentiation ◽  
Cell Types ◽  
Stem Cell Marker ◽  
Differentiation Potential ◽  
Multipotent Stem Cells ◽  
Decidua Basalis

Human multipotent stem cell-based therapies have shown remarkable potential in regenerative medicine and tissue engineering applications due to their abilities of self-renewal and differentiation into multiple adult cell types under appropriate conditions. Presently, human multipotent stem cells can be isolated from different sources, but variation among their basic biology can result in suboptimal selection of seed cells in preclinical and clinical research. Thus, the goal of this study was to compare the biological characteristics of multipotent stem cells isolated from human bone marrow, placental decidua basalis, and urine, respectively. First, we found that urine-derived stem cells (USCs) displayed different morphologies compared with other stem cell types. USCs and placenta decidua basalis-derived mesenchymal stem cells (PDB-MSCs) had superior proliferation ability in contrast to bone marrow-derived mesenchymal stem cells (BMSCs); these cells grew to have the highest colony-forming unit (CFU) counts. In phenotypic analysis using flow cytometry, similarity among all stem cell marker expression was found, excluding CD29 and CD105. Regarding stem cell differentiation capability, USCs were observed to have better adipogenic and endothelial abilities as well as vascularization potential compared to BMSCs and PDB-MSCs. As for osteogenic and chondrogenic induction, BMSCs were superior to all three stem cell types. Future therapeutic indications and clinical applications of BMSCs, PDB-MSCs, and USCs should be based on their characteristics, such as growth kinetics and differentiation capabilities.

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