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Special Issue "Role and Application of Stem Cells in Regenerative Medicine"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 31 August 2019.

Special Issue Editors

Guest Editor
Prof. Dr. Oriana Trubiani

Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio”, Chieti-Pescara, via dei Vestini, 31, 66100 Chieti, Italy
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Interests: stem cells; dentistry; regenerative medicine
Co-Guest Editor
Dr. Jacopo Pizzicannella

ASL02 Lanciano-Vasto Chieti, Ss. Annunziata Hospital, Chieti, Italy
E-Mail
Interests: translational medicine; stem cells biology; oral stem cells; regenerative medicine
Co-Guest Editor
Dr. Francesca Diomede

Departmento of Medical, Oral and Biotechnological Sciences, University "G d'Annunzio" Chieti, Italy
Website | E-Mail
Interests: ranslational medicine; stem cells biology; oral stem cells; regenerative medicine

Special Issue Information

Dear Colleagues,

Mesenchymal stem cells (MSCs) are currently being used in preclinical and clinical trials for their aptitude to promote wound healing and tissue regeneration.

In particular, oral-derived Mesenchymal Stem Cells (oral-MSCs) represent accessible sites available for stem cell collection and they can be used in regenerative medicine, avoiding the ethical concerns. They can be derived from different oral tissues, such as human exfoliated deciduous teeth (SHED), periodontal ligament (PDLSCs), dental follicle progenitor cells (DFPCs), apical papilla (SCAP), dental pulp (DPSCs) and gingival tissue (GMSCs), and posses multipotential, proliferation and differentiation abilities. Moreover, oral-MSCs represent paracrine and immunomodulatory capacity, an innovative tool for the treatment of various degenerative and traumathic processes, including skeletal and maxilla-facial degeneration, trauma or ischemia injuries, neurodegenerative, as well as immune disorders.

This Special Issue, “Role and Application of Stem Cells in Regenerative Medicine”, of the International Journal of Molecular Sciences will comprise a selection of research papers and reviews that will contribute in the evaluation of aptitude, in particular, of oral-MSCs and their secretome in terms of tissue regeneration, as a starting point for the fabrication of 3D-living constructs for future clinical applications.

Moreover, to better understand the molecular mechanisms involved in tissue regeneration, in vitro and in vivo studies will provide a possible high impact in the development of stem cell based regeneration strategies and in the identification of the key biological regulation processes that remain uncovered.

Prof. Dr. Oriana Trubiani
Dr. Jacopo Pizzicannella
Dr. Francesca Diomede

Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • Mesenchymal stem cells
  • Tissue reggeneration
  • Regenerative medicine
  • Immunomodulatory process

Published Papers (27 papers)

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Research

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Open AccessArticle
Autologous Cellular Method Using Micrografts of Human Adipose Tissue Derived Follicle Stem Cells in Androgenic Alopecia
Int. J. Mol. Sci. 2019, 20(14), 3446; https://doi.org/10.3390/ijms20143446
Received: 27 June 2019 / Revised: 8 July 2019 / Accepted: 10 July 2019 / Published: 13 July 2019
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Abstract
Hair bio-engineering has risen at the crossing point of various manipulations to meet a clinical requirement for innovations to advance hair growth. The authors reported the microscopic and trichoscopic results of an autologous cell biological technique to compare, through histological, immunocytochemistry, and cytospin [...] Read more.
Hair bio-engineering has risen at the crossing point of various manipulations to meet a clinical requirement for innovations to advance hair growth. The authors reported the microscopic and trichoscopic results of an autologous cell biological technique to compare, through histological, immunocytochemistry, and cytospin analysis, hair re-growth obtained by micro-grafts from scalp tissue containing Human Intra- and Extra-Dermal Adipose Tissue-Derived Hair Follicle Stem Cells (HD-AFSCs) versus placebo (saline solution). An autologous solution of micro-grafts was obtained from mechanical fragmentation and centrifugation of scalp biopsy’s (2 × 2 mm) using “Gentile protocol”. The micro-grafts solution was mechanically infiltrated on half of the selected patients’ scalps with Androgenic Alopecia (Norwood–Hamilton 2–5 and Ludwig 1–2). The other half was infiltrated with saline solution. Three injections were performed to each patient at 45-day intervals. Of the 35 patients who were enrolled, 1 was excluded and 1 was rejected. 23 and 44 weeks after the last micro graft’s injections, the patients displayed a hair density improvement, with a mean increment of 33% ± 7.5% and 27% ± 3.5% respectively, contrasted with baseline values, for the treated region. Microscopic assessment appeared, in scalp biopsies, to show an expansion in the number of hair follicles per mm2 following 11 months from the last micro-grafts application compared with baseline (1.4 + 0.27 versus 0.46 + 0.15, respectively; p < 0.05). HD-AFSCs contained in micro-grafts may represent a safe and effective alternative therapy option against hair loss. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
Chondrogenic Differentiation of Pluripotent Stem Cells under Controllable Serum-Free Conditions
Int. J. Mol. Sci. 2019, 20(11), 2711; https://doi.org/10.3390/ijms20112711
Received: 17 April 2019 / Revised: 24 May 2019 / Accepted: 31 May 2019 / Published: 2 June 2019
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Abstract
The repair of damaged articular cartilage using currently available implantation techniques is not sufficient for the full recovery of patients. Pluripotent stem cells (iPSC)-based therapies could bring new perspectives in the treatment of joint diseases. A number of protocols of in vitro differentiation [...] Read more.
The repair of damaged articular cartilage using currently available implantation techniques is not sufficient for the full recovery of patients. Pluripotent stem cells (iPSC)-based therapies could bring new perspectives in the treatment of joint diseases. A number of protocols of in vitro differentiation of iPSC in chondrocytes for regenerative purposes have been recently described. However, in order to use these cells in clinics, the elimination of animal serum and feeder cells is essential. In our study, a strictly defined and controllable protocol was designed for the differentiation of pluripotent stem cells (BG01V, ND 41658*H, GPCCi001-A) in chondrocyte-like cells in serum- and a feeder cell-free system, using the embryoid bodies step. The extension of the protocol and culture conditions (monolayer versus 3D culture) was also tested after the initial 21 days of chondrogenic differentiation. Promotion of the chondrogenic differentiation in 3D culture via the elevated expression of genes related to chondrogenesis was achieved. Using immunofluorescence and immunohistochemistry staining techniques, the increased deposition of the specific extracellular matrix was indicated. As a result, chondrocyte-like cells in the early stages of their differentiation using pellet culture under fully controlled and defined conditions were obtained. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
Expression of Musashi-1 During Osteogenic Differentiation of Oral MSC: An In Vitro Study
Int. J. Mol. Sci. 2019, 20(9), 2171; https://doi.org/10.3390/ijms20092171
Received: 26 March 2019 / Revised: 26 April 2019 / Accepted: 29 April 2019 / Published: 2 May 2019
Cited by 1 | PDF Full-text (2876 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Background: Musashi-1 (MSI1) is a negative regulator of mesenchymal stromal cell (MSC) differentiation which in turn favors cell proliferation. However, little is known about its expression by MSC from the oral cavity and in the context of osteogenic differentiation. Aim: The aim of [...] Read more.
Background: Musashi-1 (MSI1) is a negative regulator of mesenchymal stromal cell (MSC) differentiation which in turn favors cell proliferation. However, little is known about its expression by MSC from the oral cavity and in the context of osteogenic differentiation. Aim: The aim of this study was to analyze the expression of MSI1 in the context of osteogenic differentiation of MSC derived from the oral cavity. Material/methods: For this in vitro study, MSC were isolated from six different origins of the oral cavity. They were extensively characterized in terms of proliferative and clonogenicity potential, expression of stemness genes (MYC, NANOG, POU5F1, and SOX2), expression of surface markers (CD73, CD90, CD105, CD14, CD31, CD34, and CD45) and adipo-, chondro- and osteogenic differentiation potential. Then, osteogenic differentiation was induced and the expression of MSI1 mRNA and other relevant markers of osteogenic differentiation, including RUNX2 and Periostin, were also evaluated. Results: Cell populations from the alveolar bone (pristine or previously grafted with xenograft), dental follicle, dental germ, dental pulp, and periodontal ligament were obtained. The analysis of proliferative and clonogenicity potential, expression of the stemness genes, expression of surface markers, and differentiation potential showed similar characteristics to those of previously published MSC from the umbilical cord. Under osteogenic differentiation conditions, all MSC populations formed calcium deposits and expressed higher SPARC. Over time, the expression of MSI1 followed different patterns for the different MSC populations. It was not significantly different than the expression of RUNX2. In contrast, the expression of MSI1 and POSTN and RUNX2 were statistically different in most MSC populations. Conclusion: In the current study, a similar expression pattern of MSI1 and RUNX2 during in vitro osteogenic differentiation was identified. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
Oxidative Stress-Tolerant Stem Cells from Human Exfoliated Deciduous Teeth Decrease Hydrogen Peroxide-Induced Damage in Organotypic Brain Slice Cultures from Adult Mice
Int. J. Mol. Sci. 2019, 20(8), 1858; https://doi.org/10.3390/ijms20081858
Received: 21 March 2019 / Revised: 11 April 2019 / Accepted: 12 April 2019 / Published: 15 April 2019
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Abstract
Oxidative stress causes severe tissue injury of the central nervous system in ischemic brain damage (IBD), traumatic brain injury (TBI) and neurodegenerative disorders. In this study, we used hydrogen peroxide (H2O2) to induce oxidative stress in organotypic brain slice [...] Read more.
Oxidative stress causes severe tissue injury of the central nervous system in ischemic brain damage (IBD), traumatic brain injury (TBI) and neurodegenerative disorders. In this study, we used hydrogen peroxide (H2O2) to induce oxidative stress in organotypic brain slice cultures (OBSCs), and investigated the protective effects of oxidative stress-tolerant (OST) stem cells harvested from human exfoliated deciduous teeth (SHED) which were co-cultivated with OBSCs. Using presto blue assay and immunostaining, we demonstrated that both normal SHED and OST-SHED could prevent H2O2-induced cell death, and increase the numbers of mature neuron and neuronal progenitors in the hippocampus of OBSCs. During co-cultivation, OST-SHED, but not normal SHED, exhibited neuronal cell morphology and expressed neuronal markers. Results from ELISA showed that both normal SHED and OST-SHED significantly decreased oxidative DNA damage in H2O2-treated OBSCs. SHED could also produce neurotrophic factor BDNF (brain derived neurotrophic factor) and promoted the production of IL-6 in OBSCs. Although OST-SHED had lower cell viability, the neuronal protection of OST-SHED was significantly superior to that of normal SHED. Our findings suggest that SHED, especially OST-SHED, could prevent oxidative stress induced brain damage. OST-SHED can be explored as a new therapeutic tool for IBD, TBI and neurodegenerative disorders. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
Conditioned Medium from Human Mesenchymal Stromal Cells: Towards the Clinical Translation
Int. J. Mol. Sci. 2019, 20(7), 1656; https://doi.org/10.3390/ijms20071656
Received: 20 March 2019 / Revised: 29 March 2019 / Accepted: 30 March 2019 / Published: 3 April 2019
Cited by 1 | PDF Full-text (2997 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Mesenchymal stem/stromal cells (MSC) remain a promising tool for regenerative medicine as the efficacy of MSC-based cell therapy has been demonstrated for a broad spectrum of indications. Their therapeutic potency is mainly associated with their ability to secrete multiple factors critical for tissue [...] Read more.
Mesenchymal stem/stromal cells (MSC) remain a promising tool for regenerative medicine as the efficacy of MSC-based cell therapy has been demonstrated for a broad spectrum of indications. Their therapeutic potency is mainly associated with their ability to secrete multiple factors critical for tissue regeneration. Due to comparable effects along with superior safety MSC conditioned medium (MSC-CM) containing a complex of MSC-secreted products is considered a reasonable alternative to cell therapy. However, the lack of standards regulating bioprocessing, use of proper auxiliary materials, and quality control complicates the development of MSC secretome-based therapeutics. In this study, we suggested several approaches addressing these issues. We manufactured 36 MSC-CM samples based on different xeno-free serum-free chemically defined media (DMEM-LG or MSC NutriStem® XF) using original protocols and considered total concentrations of regeneration-associated paracrine factors secreted by human adipose-derived MSC at each time-point of conditioning. Using regression analysis, we retrospectively predicted associations between concentrations of several components of MSC-CM and its biological activity to stimulate human dermal fibroblast and endothelial cell migration in vitro as routine examples of potency assays for cell-based products. We also demonstrated that the cell culture medium might affect MSC-CM biological activity to varying degrees depending on the potency assay type. Furthermore, we showed that regression analysis might help to overcome donor variability. The suggested approaches might be successfully applied for other cell types if their secretome was shown to be promising for application in regenerative medicine. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
Downregulation of the Netrin-1 Receptor UNC5b Underlies Increased Placental Angiogenesis in Human Gestational Diabetes Mellitus
Int. J. Mol. Sci. 2019, 20(6), 1408; https://doi.org/10.3390/ijms20061408
Received: 12 December 2018 / Revised: 28 January 2019 / Accepted: 31 January 2019 / Published: 20 March 2019
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Abstract
Gestational diabetes mellitus (GDM) is a common metabolic disorder, defined by high blood glucose levels during pregnancy, which affects foetal and post-natal development. However, the cellular and molecular mechanisms of this detrimental condition are still poorly understood. A dysregulation in circulating angiogenic trophic [...] Read more.
Gestational diabetes mellitus (GDM) is a common metabolic disorder, defined by high blood glucose levels during pregnancy, which affects foetal and post-natal development. However, the cellular and molecular mechanisms of this detrimental condition are still poorly understood. A dysregulation in circulating angiogenic trophic factors, due to a dysfunction of the feto-placental unit, has been proposed to underlie GDM. But even the detailed study of canonical pro-angiogenic factors like vascular endothelial growth factor (VEGF) or basic Fibroblast Growth Factor (bFGF) has not been able to fully explain this detrimental condition during pregnancy. Netrins are non-canonical angiogenic ligands produced by the stroma have shown to be important in placental angiogenesis. In order to address the potential role of Netrin signalling in GDM, we tested the effect of Netrin-1, the most investigated member of the family, produced by Wharton’s Jelly Mesenchymal Stem Cells (WJ-MSC), on Human Umbilical Vein Endothelial Cells (HUVEC) angiogenesis. WJ-MSC and HUVEC primary cell cultures from either healthy or GDM pregnancies were exposed to physiological (5 mM) or high (25 mM) d-glucose. Our results reveal that Netrin-1 is secreted by WJ-MSC from healthy and GDM and both expression and secretion of the ligand do not change with distinct experimental glucose conditions. Noteworthy, the expression of its anti-angiogenic receptor UNC5b is reduced in GDM HUVEC compared with its expression in healthy HUVEC, accounting for an increased Netrin-1 signalling in these cells. Consistently, in healthy HUVEC, UNC5b overexpression induces cell retraction of the sprouting phenotype. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
Growth Factor Screening in Dystrophic Muscles Reveals PDGFB/PDGFRB-Mediated Migration of Interstitial Stem Cells
Int. J. Mol. Sci. 2019, 20(5), 1118; https://doi.org/10.3390/ijms20051118
Received: 31 January 2019 / Revised: 25 February 2019 / Accepted: 26 February 2019 / Published: 5 March 2019
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Abstract
Progressive muscle degeneration followed by dilated cardiomyopathy is a hallmark of muscular dystrophy. Stem cell therapy is suggested to replace diseased myofibers by healthy myofibers, although so far, we are faced by low efficiencies of migration and engraftment of stem cells. Chemokines are [...] Read more.
Progressive muscle degeneration followed by dilated cardiomyopathy is a hallmark of muscular dystrophy. Stem cell therapy is suggested to replace diseased myofibers by healthy myofibers, although so far, we are faced by low efficiencies of migration and engraftment of stem cells. Chemokines are signalling proteins guiding cell migration and have been shown to tightly regulate muscle tissue repair. We sought to determine which chemokines are expressed in dystrophic muscles undergoing tissue remodelling. Therefore, we analysed the expression of chemokines and chemokine receptors in skeletal and cardiac muscles from Sarcoglycan-α null, Sarcoglycan-β null and immunodeficient Sgcβ-null mice. We found that several chemokines are dysregulated in dystrophic muscles. We further show that one of these, platelet-derived growth factor-B, promotes interstitial stem cell migration. This finding provides perspective to an approachable mechanism for improving stem cell homing towards dystrophic muscles. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
Integrated Multi-Assay Culture Model for Stem Cell Chondrogenic Differentiation
Int. J. Mol. Sci. 2019, 20(4), 951; https://doi.org/10.3390/ijms20040951
Received: 16 January 2019 / Revised: 15 February 2019 / Accepted: 17 February 2019 / Published: 22 February 2019
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Abstract
Recent osteochondral repair strategies highlight the promise of mesenchymal progenitors, an accessible stem cell source with osteogenic and chondrogenic potential, used in conjunction with biomaterials for tissue engineering. For this, regenerative medicine approaches require robust models to ensure selected cell populations can generate [...] Read more.
Recent osteochondral repair strategies highlight the promise of mesenchymal progenitors, an accessible stem cell source with osteogenic and chondrogenic potential, used in conjunction with biomaterials for tissue engineering. For this, regenerative medicine approaches require robust models to ensure selected cell populations can generate the desired cell type in a reproducible and measurable manner. Techniques for in vitro chondrogenic differentiation are well-established but largely qualitative, relying on sample staining and imaging. To facilitate the in vitro screening of pro-chondrogenic treatments, a 3D micropellet culture combined with three quantitative GAG assays has been developed, with a fourth parallel assay measuring sample content to enable normalisation. The effect of transforming growth factor beta (TGF-β) used to validate this culture format produced a measurable increase in proteoglycan production in the parallel assays, in both 2D and 3D culture configurations. When compared to traditional micropellets, the monolayer format appeared less able to detect changes in cell differentiation, however in-well 3D cultures displayed a significant differential response. Effects on collagen 2 expression confirmed these observations. Based on these results, a microplate format was optimised for 3D culture, in a high-throughput in-well configuration. This model showed improved sensitivity and confirmed the 3D micropellet in-well quantitative assays as an effective differentiation format compatible with streamlined, high-throughput chondrogenic screens. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
MIST1, an Inductive Signal for Salivary Amylase in Mesenchymal Stem Cells
Int. J. Mol. Sci. 2019, 20(3), 767; https://doi.org/10.3390/ijms20030767
Received: 23 January 2019 / Revised: 5 February 2019 / Accepted: 5 February 2019 / Published: 12 February 2019
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Abstract
Sjögren’s syndrome (SjS) is an autoimmune disease that destroys the salivary glands and results in severe dry mouth. Mesenchymal stem cell (MSC) transplantation has been recently proposed as a promising therapy for restoring cells in multiple degenerative diseases. We have recently utilized advanced [...] Read more.
Sjögren’s syndrome (SjS) is an autoimmune disease that destroys the salivary glands and results in severe dry mouth. Mesenchymal stem cell (MSC) transplantation has been recently proposed as a promising therapy for restoring cells in multiple degenerative diseases. We have recently utilized advanced proteomics biochemical assays to identify the key molecules involved in the mesenchymal-epithelial transition (MET) of co-cultured mouse bone-marrow-derived MSCs mMSCs with primary salivary gland cells. Among the multiple transcription factors (TFs) that were differentially expressed, two major TFs were selected: muscle, intestine, and stomach expression-1 (MIST1) and transcription factor E2a (TCF3). These factors were assessed in the current study for their ability to drive the expression of acinar cell marker, alpha-salivary amylase 1 (AMY1), and ductal cell marker, cytokeratin19 (CK19), in vitro. Overexpression of MIST1-induced AMY1 expression while it had little effect on CK19 expression. In contrast, TCF3 induced neither of those cellular markers. Furthermore, we have identified that mMSCs express muscarinic-type 3 receptor (M3R) mainly in the cytoplasm and aquaporin 5 (AQP5) in the nucleus. While MIST1 did not alter M3R levels in mMSCs, a TCF3 overexpression downregulated M3R expressions in mMSCs. The mechanisms for such differential regulation of glandular markers by these TFs warrant further investigation. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
The Fate of Transplanted Periodontal Ligament Stem Cells in Surgically Created Periodontal Defects in Rats
Int. J. Mol. Sci. 2019, 20(1), 192; https://doi.org/10.3390/ijms20010192
Received: 28 November 2018 / Revised: 25 December 2018 / Accepted: 28 December 2018 / Published: 7 January 2019
Cited by 2 | PDF Full-text (3145 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Periodontal disease is chronic inflammation that leads to the destruction of tooth-supporting periodontal tissues. We devised a novel method (“cell transfer technology”) to transfer cells onto a scaffold surface and reported the potential of the technique for regenerative medicine. The aim of this [...] Read more.
Periodontal disease is chronic inflammation that leads to the destruction of tooth-supporting periodontal tissues. We devised a novel method (“cell transfer technology”) to transfer cells onto a scaffold surface and reported the potential of the technique for regenerative medicine. The aim of this study is to examine the efficacy of this technique in periodontal regeneration and the fate of transplanted cells. Human periodontal ligament stem cells (PDLSCs) were transferred to decellularized amniotic membrane and transplanted into periodontal defects in rats. Regeneration of tissues was examined by microcomputed tomography and histological observation. The fate of transplanted PDLSCs was traced using PKH26 and human Alu sequence detection by PCR. Imaging showed more bone in PDLSC-transplanted defects than those in control (amnion only). Histological examination confirmed the enhanced periodontal tissue formation in PDLSC defects. New formation of cementum, periodontal ligament, and bone were prominently observed in PDLSC defects. PKH26-labeled PDLSCs were found at limited areas in regenerated periodontal tissues. Human Alu sequence detection revealed that the level of Alu sequence was not increased, but rather decreased. This study describes a novel stem cell transplantation strategy for periodontal disease using the cell transfer technology and offers new insight for cell-based periodontal regeneration. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
Therapeutic Potential of Autologous Adipose-Derived Stem Cells for the Treatment of Liver Disease
Int. J. Mol. Sci. 2018, 19(12), 4064; https://doi.org/10.3390/ijms19124064
Received: 7 October 2018 / Revised: 30 November 2018 / Accepted: 12 December 2018 / Published: 15 December 2018
Cited by 2 | PDF Full-text (5623 KB) | HTML Full-text | XML Full-text
Abstract
Currently, the most effective therapy for liver diseases is liver transplantation, but its use is limited by organ donor shortage, economic reasons, and the requirement for lifelong immunosuppression. Mesenchymal stem cell (MSC) transplantation represents a promising alternative for treating liver pathologies in both [...] Read more.
Currently, the most effective therapy for liver diseases is liver transplantation, but its use is limited by organ donor shortage, economic reasons, and the requirement for lifelong immunosuppression. Mesenchymal stem cell (MSC) transplantation represents a promising alternative for treating liver pathologies in both human and veterinary medicine. Interestingly, these pathologies appear with a common clinical and pathological profile in the human and canine species; as a consequence, dogs may be a spontaneous model for clinical investigations in humans. The aim of this work was to characterize canine adipose-derived MSCs (cADSCs) and compare them to their human counterpart (hADSCs) in order to support the application of the canine model in cell-based therapy of liver diseases. Both cADSCs and hADSCs were successfully isolated from adipose tissue samples. The two cell populations shared a common fibroblast-like morphology, expression of stemness surface markers, and proliferation rate. When examining multilineage differentiation abilities, cADSCs showed lower adipogenic potential and higher osteogenic differentiation than human cells. Both cell populations retained high viability when kept in PBS at controlled temperature and up to 72 h, indicating the possibility of short-term storage and transportation. In addition, we evaluated the efficacy of autologous ADSCs transplantation in dogs with liver diseases. All animals exhibited significantly improved liver function, as evidenced by lower liver biomarkers levels measured after cells transplantation and evaluation of cytological specimens. These beneficial effects seem to be related to the immunomodulatory properties of stem cells. We therefore believe that such an approach could be a starting point for translating the results to the human clinical practice in future. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
MicroRNA 210 Mediates VEGF Upregulation in Human Periodontal Ligament Stem Cells Cultured on 3DHydroxyapatite Ceramic Scaffold
Int. J. Mol. Sci. 2018, 19(12), 3916; https://doi.org/10.3390/ijms19123916
Received: 23 November 2018 / Revised: 3 December 2018 / Accepted: 5 December 2018 / Published: 6 December 2018
Cited by 11 | PDF Full-text (4054 KB) | HTML Full-text | XML Full-text
Abstract
The aim of the present research was the evaluation of the behavior of human periodontal ligament stem cells (hPDLSCs), cultured in presence of Endobon® Xenograft Granules (G), a fully deproteinated hydroxyapatite ceramic scaffold derived from cancellous bovine bone. hPDLSCs were seeded with [...] Read more.
The aim of the present research was the evaluation of the behavior of human periodontal ligament stem cells (hPDLSCs), cultured in presence of Endobon® Xenograft Granules (G), a fully deproteinated hydroxyapatite ceramic scaffold derived from cancellous bovine bone. hPDLSCs were seeded with and without G for 24 h to 1 week. The cell growth, morphological features, adhesiveness, differentiation ability, modulation of miR-210 and Vascular Endothelial Growth Factor (VEGF) secretion were analyzed by means of MTT assay, Scanning Electron Microscopy (SEM), Confocal Laser Scanning Microscopy (CLSM), Alizarin Red S assay, RT-PCR and ELISA test, respectively. hPDLSCs grown on the biomaterial showed the ability to form focal adhesion on the substrate, as demonstrated by vinculin expression. These data were supported by SEM analysis showing that an adhesiveness process associated to cell growth occurs between cells and biomaterials. The osteogenic differentiation, evaluated by morphological, biochemical, and RT-PCR analysis, was pronounced in the hPDLSCs grown in the three-dimensional inorganic bovine bone substitute in the presence of osteoinductive conditions. In addition, an upregulation of miR-210 and VEGF was evident in cells cultured in presence of the biomaterial. Our results inspire us to consider granules not only an adequate biocompatible three-dimensional biomaterial, but also an effective inductor of miR-210 and VEGF; in fact, the involvement of miR-210 in VEGF secretion could offer a novel regulatory system in the early steps of the bone-regeneration process. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
Engineered Mesenchymal Stem Cells Expressing Stromal Cell-derived Factor-1 Improve Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats
Int. J. Mol. Sci. 2018, 19(12), 3730; https://doi.org/10.3390/ijms19123730
Received: 25 September 2018 / Revised: 20 November 2018 / Accepted: 21 November 2018 / Published: 23 November 2018
Cited by 2 | PDF Full-text (4713 KB) | HTML Full-text | XML Full-text
Abstract
Effective therapies for erectile dysfunction (ED) associated with diabetes mellitus (DM) are needed. In this study, the effects of stromal cell-derived factor-1 (SDF-1)-expressing engineered mesenchymal stem cells (SDF-1 eMSCs) and the relevant mechanisms in the corpus cavernosum of a streptozotocin (STZ)-induced DM ED [...] Read more.
Effective therapies for erectile dysfunction (ED) associated with diabetes mellitus (DM) are needed. In this study, the effects of stromal cell-derived factor-1 (SDF-1)-expressing engineered mesenchymal stem cells (SDF-1 eMSCs) and the relevant mechanisms in the corpus cavernosum of a streptozotocin (STZ)-induced DM ED rat model were evaluated. In a randomized controlled trial, Sprague–Dawley (SD) rats (n = 48) were divided into four groups (n = 12/group): Normal (control), DM ED (diabetes induced by STZ), DM ED + BM-MSC (treated with bone marrow [BM]-derived MSCs), and DM ED + SDF-1 eMSC (treated with SDF-1-expressing BM-MSCs). After four weeks, intracavernosal pressure (ICP), an indicator of erectile function, was 0.75 ± 0.07 in the normal group, 0.27 ± 0.08 in the DM ED group, 0.42 ± 0.11 in the DM ED + BM-MSC group, and 0.58 ± 0.11 in the DM ED + SDF-1 eMSC group. BM-MSCs, especially SDF-1 eMSCs, improved ED (p < 0.05). SDF-1 eMSC treatment improved the smooth muscle content in the corpus cavernosum (p < 0.05). As SDF-1 expression increased, ED recovery improved. In the SDF-1 eMSC group, levels of neuronal nitric oxide synthase (nNOS) and phosphorylated endothelial NOS (p-eNOS) were higher than those in other groups (p < 0.05). In addition, high stromal cell-derived factor-1 (SDF-1) expression was associated with increased vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in DM ED rats (p < 0.05). Higher levels of phosphorylated protein kinase B (p-AKT)/protein kinase B (AKT) (p < 0.05) and B-cell lymphoma-2 (Bcl-2) and lower levels of the apoptosis factors Bcl2-associated x (Bax) and caspase-3 were observed in the MSC-treated group than in the DM ED group (p < 0.05). SDF-1 eMSCs showed beneficial effects on recovery from erectile function. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
Mechanistic Analysis of Physicochemical Cues in Promoting Human Pluripotent Stem Cell Self-Renewal and Metabolism
Int. J. Mol. Sci. 2018, 19(11), 3459; https://doi.org/10.3390/ijms19113459
Received: 6 October 2018 / Revised: 27 October 2018 / Accepted: 1 November 2018 / Published: 4 November 2018
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Abstract
We have previously reported that a porous membrane of polyethylene terephthalate (PET) enables significant augmentation of human pluripotent stem cell (hPSC) proliferation and differentiation. The interaction between hPSCs and the PET surface induces β-catenin-mediated wingless/integrated (Wnt) signaling, leading to upregulation of [...] Read more.
We have previously reported that a porous membrane of polyethylene terephthalate (PET) enables significant augmentation of human pluripotent stem cell (hPSC) proliferation and differentiation. The interaction between hPSCs and the PET surface induces β-catenin-mediated wingless/integrated (Wnt) signaling, leading to upregulation of the expression of adhesion molecules in hPSCs. In this study, we sought to unveil mechanisms underlying the role of the PET membrane in hPSC self-renewal and metabolism. We discovered that physicochemical cues of the PET membrane considerably alter hPSC metabolism by increasing the cell yield and suppressing the generation of toxic byproduct, indicating an effective cell self-renewal and a less apoptotic culture environment in the membrane culture system. Furthermore, we discovered that a caspase-8 medicated apoptotic pathway plays a profound role in obstructing hPSCs grown on a traditional tissue culture plate (TCP). Treating hPSCs seeded on a TCP surface with a caspase-8 inhibitor significantly suppressed cellular apoptotic pathway and improved cell proliferation and metabolism. Our experimental results provided valuable insights into signal pathways influencing hPSC self-renewal during routine maintenance and expansion, which would shed light on large-scale preparation of hPSCs for clinical applications. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
Injectable Systems for Intra-Articular Delivery of Mesenchymal Stromal Cells for Cartilage Treatment: A Systematic Review of Preclinical and Clinical Evidence
Int. J. Mol. Sci. 2018, 19(11), 3322; https://doi.org/10.3390/ijms19113322
Received: 13 September 2018 / Revised: 19 October 2018 / Accepted: 20 October 2018 / Published: 25 October 2018
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Abstract
Stem cell-based therapy is a promising approach to treat cartilage lesions and clinical benefits have been reported in a number of studies. However, the efficacy of cell injection procedures may be impaired by cell manipulation and damage as well as by cell dissemination [...] Read more.
Stem cell-based therapy is a promising approach to treat cartilage lesions and clinical benefits have been reported in a number of studies. However, the efficacy of cell injection procedures may be impaired by cell manipulation and damage as well as by cell dissemination to non-target tissues. To overcome such issues, mesenchymal stromal cell (MSC) delivery may be performed using injectable vehicles as containment systems that further provide a favorable cell microenvironment. The aim of this systematic review was to analyze the preclinical and clinical literature on platelet-rich plasma (PRP), hyaluronic acid (HA), and hydrogels for the delivery of MSCs. The systematic literature search was performed using the PubMed and Web of science databases with the following string: “(stem cells injection) AND (platelet rich plasma OR PRP OR platelet concentrate OR biomaterials OR hyaluronic acid OR hydrogels)”: 40 studies (19 preclinical and 21 clinical) met the inclusion criteria. This review revealed an increasing interest on the use of injectable agents for MSC delivery. However, while negligible adverse events and promising clinical outcomes were generally reported, the prevalence of low quality studies hinders the possibility to demonstrate the real benefits of using such injectable systems. Specific studies must be designed to clearly demonstrate the added benefits of these systems to deliver MSCs for the treatment of cartilage lesions and osteoarthritis. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle
Treatment of Periodontal Ligament Stem Cells with MOR and CBD Promotes Cell Survival and Neuronal Differentiation via the PI3K/Akt/mTOR Pathway
Int. J. Mol. Sci. 2018, 19(8), 2341; https://doi.org/10.3390/ijms19082341
Received: 11 July 2018 / Revised: 31 July 2018 / Accepted: 6 August 2018 / Published: 9 August 2018
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Abstract
Periodontal ligament mesenchymal stem cells (hPDLSCs), as well as all mesenchymal stem cells, show self-renewal, clonogenicity, and multi-tissue differentiation proprieties and can represent a valid support for regenerative medicine. We treated hPDLSCs with a combination of Moringin (MOR) and Cannabidiol (CBD), in order [...] Read more.
Periodontal ligament mesenchymal stem cells (hPDLSCs), as well as all mesenchymal stem cells, show self-renewal, clonogenicity, and multi-tissue differentiation proprieties and can represent a valid support for regenerative medicine. We treated hPDLSCs with a combination of Moringin (MOR) and Cannabidiol (CBD), in order to understand if treatment could improve their survival and their in vitro differentiation capacity. Stem cells survival is fundamental to achieve a successful therapy outcome in the re-implanted tissue of patients. Through NGS transcriptome analysis, we found that combined treatment increased hPDLSCs survival, by inhibition of apoptosis as demonstrated by enhanced expression of anti-apoptotic genes and reduction of pro-apoptotic ones. Moreover, we investigated the possible involvement of PI3K/Akt/mTOR pathway, emphasizing a differential gene expression between treated and untreated cells. Furthermore, hPDLSCs were cultured for 48 h in the presence or absence of CBD and MOR and, after confirming the cellular viability through MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide) assay, we examined the presence of neuronal markers, through immunofluorescence analysis. We found an increased expression of Nestin and GAP43 (growth associated protein 43) in treated cells. In conclusion, hPDLSCs treated with Moringin and Cannabidiol showed an improved survival capacity and neuronal differentiation potential. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Review

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Open AccessReview
The Role of Mesenchymal Stem Cells in Radiation-Induced Lung Fibrosis
Int. J. Mol. Sci. 2019, 20(16), 3876; https://doi.org/10.3390/ijms20163876
Received: 22 July 2019 / Accepted: 5 August 2019 / Published: 8 August 2019
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Abstract
Radiation therapy is one of the most important treatment modalities for thoracic tumors. Despite significant advances in radiation techniques, radiation-induced lung injury (RILI) still occurs in up to 30% of patients undergoing thoracic radiotherapy, and therefore remains the main dose-limiting obstacle. RILI is [...] Read more.
Radiation therapy is one of the most important treatment modalities for thoracic tumors. Despite significant advances in radiation techniques, radiation-induced lung injury (RILI) still occurs in up to 30% of patients undergoing thoracic radiotherapy, and therefore remains the main dose-limiting obstacle. RILI is a potentially lethal clinical complication of radiotherapy that has 2 main stages: an acute stage defined as radiation pneumonitis, and a late stage defined as radiation-induced lung fibrosis. Patients who develop lung fibrosis have a reduced quality of life with progressive and irreversible organ malfunction. Currently, the most effective intervention for the treatment of lung fibrosis is lung transplantation, but the lack of available lungs and transplantation-related complications severely limits the success of this procedure. Over the last few decades, advances have been reported in the use of mesenchymal stem cells (MSCs) for lung tissue repair and regeneration. MSCs not only replace damaged lung epithelial cells but also promote tissue repair through the secretion of anti-inflammatory and anti-fibrotic factors. Here, we present an overview of MSC-based therapy for radiation-induced lung fibrosis, focusing in particular on the molecular mechanisms involved and describing the most recent preclinical and clinical studies carried out in the field. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessReview
Application of Periodontal Ligament-Derived Multipotent Mesenchymal Stromal Cell Sheets for Periodontal Regeneration
Int. J. Mol. Sci. 2019, 20(11), 2796; https://doi.org/10.3390/ijms20112796
Received: 25 April 2019 / Revised: 5 June 2019 / Accepted: 5 June 2019 / Published: 7 June 2019
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Abstract
Periodontitis is a chronic inflammatory disorder that causes destruction of the periodontal attachment apparatus including alveolar bone, the periodontal ligament, and cementum. Dental implants have been routinely installed after extraction of periodontitis-affected teeth; however, recent studies have indicated that many dental implants are [...] Read more.
Periodontitis is a chronic inflammatory disorder that causes destruction of the periodontal attachment apparatus including alveolar bone, the periodontal ligament, and cementum. Dental implants have been routinely installed after extraction of periodontitis-affected teeth; however, recent studies have indicated that many dental implants are affected by peri-implantitis, which progresses rapidly because of the failure of the immune system. Therefore, there is a renewed focus on periodontal regeneration aroundnatural teeth. To regenerate periodontal tissue, many researchers and clinicians have attempted to perform periodontal regenerative therapy using materials such as bioresorbable scaffolds, growth factors, and cells. The concept of guided tissue regeneration, by which endogenous periodontal ligament- and alveolar bone-derived cells are preferentially proliferated by barrier membranes, has proved effective, and various kinds of membranes are now commercially available. Clinical studies have shown the significance of barrier membranes for periodontal regeneration; however, the technique is indicated only for relatively small infrabony defects. Cytokine therapies have also been introduced to promote periodontal regeneration, but the indications are also for small size defects. To overcome this limitation, ex vivo expanded multipotent mesenchymal stromal cells (MSCs) have been studied. In particular, periodontal ligament-derived multipotent mesenchymal stromal cells are thought to be a responsible cell source, based on both translational and clinical studies. In this review, responsible cell sources for periodontal regeneration and their clinical applications are summarized. In addition, recent transplantation strategies and perspectives about the cytotherapeutic use of stem cells for periodontal regeneration are discussed. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessReview
The Role of the Stem Cells Therapy in the Peripheral Artery Disease
Int. J. Mol. Sci. 2019, 20(9), 2233; https://doi.org/10.3390/ijms20092233
Received: 1 April 2019 / Revised: 26 April 2019 / Accepted: 5 May 2019 / Published: 7 May 2019
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Abstract
Vascular complications of diabetes mellitus are an important issue for all clinicians involved in the management of this complex pathology. Although many therapeutic advances have been reached, peripheral arterial disease is still an unsolved problem that each year compromises the quality of life [...] Read more.
Vascular complications of diabetes mellitus are an important issue for all clinicians involved in the management of this complex pathology. Although many therapeutic advances have been reached, peripheral arterial disease is still an unsolved problem that each year compromises the quality of life and life span of affected patients. Oftentimes, patients, after ineffective attempts of revascularization, undergo greater amputations. At the moment, there is no effective and definitive treatment available. In this scenario, the therapeutic use of stem cells could be an interesting option. The aim of the present review is to gather all the best available evidence in this regard and to define a new role of the stem cells therapy in this field, from biomarker to possible therapeutic target. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessReview
Strategic Tools in Regenerative and Translational Dentistry
Int. J. Mol. Sci. 2019, 20(8), 1879; https://doi.org/10.3390/ijms20081879
Received: 29 March 2019 / Revised: 10 April 2019 / Accepted: 14 April 2019 / Published: 16 April 2019
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Abstract
Human oral-derived stem cells can be easily obtained from several oral tissues, such as dental pulp, periodontal ligament, from gingiva, or periapical cysts. Due to their differentiation potential, oral-derived mesenchymal stem cells are promising for tissue engineering and regenerative medicine. The regenerative ability [...] Read more.
Human oral-derived stem cells can be easily obtained from several oral tissues, such as dental pulp, periodontal ligament, from gingiva, or periapical cysts. Due to their differentiation potential, oral-derived mesenchymal stem cells are promising for tissue engineering and regenerative medicine. The regenerative ability showed by some oral tissues strongly depends on their sleeping adult stem cell populations that are able to repair small defects and to manage local inflammation. To date, researchers are working on effective and efficient methods to ensure safe and predictable protocols to translate stem cell research into human models. In the last decades, the challenge has been to finally use oral-derived stem cells together with biomaterials or scaffold-free techniques, to obtain strategic tools for regenerative and translational dentistry. This paper aims to give a clear point of view on state of the art developments, with some exciting insights into future strategies. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessReview
Empowering Mesenchymal Stem Cells for Ocular Degenerative Disorders
Int. J. Mol. Sci. 2019, 20(7), 1784; https://doi.org/10.3390/ijms20071784
Received: 15 February 2019 / Revised: 13 March 2019 / Accepted: 13 March 2019 / Published: 10 April 2019
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Abstract
Multipotent mesenchymal stem cells (MSCs) have been employed in numerous pre-clinical and clinical settings for various diseases. MSCs have been used in treating degenerative disorders pertaining to the eye, for example, age-related macular degeneration, glaucoma, retinitis pigmentosa, diabetic retinopathy, and optic neuritis. Despite [...] Read more.
Multipotent mesenchymal stem cells (MSCs) have been employed in numerous pre-clinical and clinical settings for various diseases. MSCs have been used in treating degenerative disorders pertaining to the eye, for example, age-related macular degeneration, glaucoma, retinitis pigmentosa, diabetic retinopathy, and optic neuritis. Despite the known therapeutic role and mechanisms of MSCs, low cell precision towards the targeted area and cell survivability at tissue needing repair often resulted in a disparity in therapeutic outcomes. In this review, we will discuss the current and feasible strategy options to enhance treatment outcomes with MSC therapy. We will review the application of various types of biomaterials and advances in nanotechnology, which have been employed on MSCs to augment cellular function and differentiation for improving treatment of visual functions. In addition, several modes of gene delivery into MSCs and the types of associated therapeutic genes that are important for modulation of ocular tissue function and repair will be highlighted. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessReview
Spare Parts from Discarded Materials: Fetal Annexes in Regenerative Medicine
Int. J. Mol. Sci. 2019, 20(7), 1573; https://doi.org/10.3390/ijms20071573
Received: 27 February 2019 / Revised: 24 March 2019 / Accepted: 26 March 2019 / Published: 29 March 2019
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Abstract
One of the main aims in regenerative medicine is to find stem cells that are easy to obtain and are safe and efficient in either an autologous or allogenic host when transplanted. This review provides an overview of the potential use of the [...] Read more.
One of the main aims in regenerative medicine is to find stem cells that are easy to obtain and are safe and efficient in either an autologous or allogenic host when transplanted. This review provides an overview of the potential use of the fetal annexes in regenerative medicine: we described the formation of the annexes, their immunological features, the new advances in the phenotypical characterization of fetal annexes-derived stem cells, the progressions obtained in the analysis of both their differentiative potential and their secretoma, and finally, the potential use of decellularized fetal membranes. Normally discarded as medical waste, the umbilical cord and perinatal tissue not only represent a rich source of stem cells but can also be used as a scaffold for regenerative medicine, providing a suitable environment for the growth and differentiation of stem cells. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessReview
Relevance of Oxygen Concentration in Stem Cell Culture for Regenerative Medicine
Int. J. Mol. Sci. 2019, 20(5), 1195; https://doi.org/10.3390/ijms20051195
Received: 11 February 2019 / Revised: 28 February 2019 / Accepted: 4 March 2019 / Published: 8 March 2019
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Abstract
The key hallmark of stem cells is their ability to self-renew while keeping a differentiation potential. Intrinsic and extrinsic cell factors may contribute to a decline in these stem cell properties, and this is of the most importance when culturing them. One of [...] Read more.
The key hallmark of stem cells is their ability to self-renew while keeping a differentiation potential. Intrinsic and extrinsic cell factors may contribute to a decline in these stem cell properties, and this is of the most importance when culturing them. One of these factors is oxygen concentration, which has been closely linked to the maintenance of stemness. The widely used environmental 21% O2 concentration represents a hyperoxic non-physiological condition, which can impair stem cell behaviour by many mechanisms. The goal of this review is to understand these mechanisms underlying the oxygen signalling pathways and their negatively-associated consequences. This may provide a rationale for culturing stem cells under physiological oxygen concentration for stem cell therapy success, in the field of tissue engineering and regenerative medicine. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessReview
Clinical Potential and Current Progress of Dental Pulp Stem Cells for Various Systemic Diseases in Regenerative Medicine: A Concise Review
Int. J. Mol. Sci. 2019, 20(5), 1132; https://doi.org/10.3390/ijms20051132
Received: 17 February 2019 / Revised: 28 February 2019 / Accepted: 1 March 2019 / Published: 6 March 2019
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Abstract
Dental pulp stem cells (DPSCs) are mesenchymal stem cells (MSCs) that have multipotent differentiation and a self-renewal ability. They have been useful not only for dental diseases, but also for systemic diseases. Extensive studies have suggested that DPSCs are effective for various diseases, [...] Read more.
Dental pulp stem cells (DPSCs) are mesenchymal stem cells (MSCs) that have multipotent differentiation and a self-renewal ability. They have been useful not only for dental diseases, but also for systemic diseases. Extensive studies have suggested that DPSCs are effective for various diseases, such as spinal cord injuries, Parkinson’s disease, Alzheimer’s disease, cerebral ischemia, myocardial infarction, muscular dystrophy, diabetes, liver diseases, eye diseases, immune diseases, and oral diseases. DPSCs have the potential for use in a cell-therapeutic paradigm shift to treat these diseases. It has also been reported that DPSCs have higher regenerative potential than the bone marrow-derived mesenchymal stem cells known as representative MSCs. Therefore, DPSCs have recently gathered much attention. In this review, the therapeutic potential of DPSCs, the latest progress in the pre-clinical study for treatment of these various systemic diseases, and the clinical applications of DPSCs in regenerative medicine, are all summarized. Although challenges, including mechanisms of the effects and establishment of cell processing and transplantation methods for clinical use, still remain, DPSCs could be promising stem cells sources for various clinical applications, because of their easy isolation by a noninvasive procedure without ethical concerns. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessReview
Enhancement of Functionality and Therapeutic Efficacy of Cell-Based Therapy Using Mesenchymal Stem Cells for Cardiovascular Disease
Int. J. Mol. Sci. 2019, 20(4), 982; https://doi.org/10.3390/ijms20040982
Received: 9 January 2019 / Revised: 20 February 2019 / Accepted: 21 February 2019 / Published: 24 February 2019
Cited by 4 | PDF Full-text (1363 KB) | HTML Full-text | XML Full-text
Abstract
Cardiovascular disease usually triggers coronary heart disease, stroke, and ischemic diseases, thus promoting the development of functional failure. Mesenchymal stem cells (MSCs) are cells that can be isolated from various human tissues, with multipotent and immunomodulatory characteristics to help damaged tissue repair and [...] Read more.
Cardiovascular disease usually triggers coronary heart disease, stroke, and ischemic diseases, thus promoting the development of functional failure. Mesenchymal stem cells (MSCs) are cells that can be isolated from various human tissues, with multipotent and immunomodulatory characteristics to help damaged tissue repair and avoidance of immune responses. Much research has proved the feasibility, safety, and efficiency of MSC-based therapy for cardiovascular disease. Despite the fact that the precise mechanism of MSCs remains unclear, their therapeutic capability to treat ischemic diseases has been tested in phase I/II clinical trials. MSCs have the potential to become an effective therapeutic strategy for the treatment of ischemic and non-ischemic cardiovascular disorders. The molecular mechanism underlying the efficacy of MSCs in promoting engraftment and accelerating the functional recovery of injury sites is still unclear. It is hypothesized that the mechanisms of paracrine effects for the cardiac repair, optimization of the niche for cell survival, and cardiac remodeling by inflammatory control are involved in the interaction between MSCs and the damaged myocardial environment. This review focuses on recent experimental and clinical findings related to cardiovascular disease. We focus on MSCs, highlighting their roles in cardiovascular disease repair, differentiation, and MSC niche, and discuss their therapeutic efficacy and the current status of MSC-based cardiovascular disease therapies. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessReview
From Neuronal Differentiation of iPSCs to 3D Neuro-Organoids: Modelling and Therapy of Neurodegenerative Diseases
Int. J. Mol. Sci. 2018, 19(12), 3972; https://doi.org/10.3390/ijms19123972
Received: 25 October 2018 / Revised: 27 November 2018 / Accepted: 7 December 2018 / Published: 10 December 2018
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Abstract
In the last decade, the advances made into the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) led to great improvements towards their use as models of diseases. In particular, in the field of neurodegenerative diseases, iPSCs technology allowed to culture [...] Read more.
In the last decade, the advances made into the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) led to great improvements towards their use as models of diseases. In particular, in the field of neurodegenerative diseases, iPSCs technology allowed to culture in vitro all types of patient-specific neural cells, facilitating not only the investigation of diseases’ etiopathology, but also the testing of new drugs and cell therapies, leading to the innovative concept of personalized medicine. Moreover, iPSCs can be differentiated and organized into 3D organoids, providing a tool which mimics the complexity of the brain’s architecture. Furthermore, recent developments in 3D bioprinting allowed the study of physiological cell-to-cell interactions, given by a combination of several biomaterials, scaffolds, and cells. This technology combines bio-plotter and biomaterials in which several types of cells, such as iPSCs or differentiated neurons, can be encapsulated in order to develop an innovative cellular model. IPSCs and 3D cell cultures technologies represent the first step towards the obtainment of a more reliable model, such as organoids, to facilitate neurodegenerative diseases’ investigation. The combination of iPSCs, 3D organoids and bioprinting will also allow the development of new therapeutic approaches. Indeed, on the one hand they will lead to the development of safer and patient-specific drugs testing but, also, they could be developed as cell-therapy for curing neurodegenerative diseases with a regenerative medicine approach. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessReview
Cell-Based Therapies for Cardiac Regeneration: A Comprehensive Review of Past and Ongoing Strategies
Int. J. Mol. Sci. 2018, 19(10), 3194; https://doi.org/10.3390/ijms19103194
Received: 2 October 2018 / Revised: 11 October 2018 / Accepted: 12 October 2018 / Published: 16 October 2018
Cited by 7 | PDF Full-text (592 KB) | HTML Full-text | XML Full-text
Abstract
Despite considerable improvements in the treatment of cardiovascular diseases, heart failure (HF) still represents one of the leading causes of death worldwide. Poor prognosis is mostly due to the limited regenerative capacity of the adult human heart, which ultimately leads to left ventricular [...] Read more.
Despite considerable improvements in the treatment of cardiovascular diseases, heart failure (HF) still represents one of the leading causes of death worldwide. Poor prognosis is mostly due to the limited regenerative capacity of the adult human heart, which ultimately leads to left ventricular dysfunction. As a consequence, heart transplantation is virtually the only alternative for many patients. Therefore, novel regenerative approaches are extremely needed, and several attempts have been performed to improve HF patients’ clinical conditions by promoting the replacement of the lost cardiomyocytes and by activating cardiac repair. In particular, cell-based therapies have been shown to possess a great potential for cardiac regeneration. Different cell types have been extensively tested in clinical trials, demonstrating consistent safety results. However, heterogeneous efficacy data have been reported, probably because precise end-points still need to be clearly defined. Moreover, the principal mechanism responsible for these beneficial effects seems to be the paracrine release of antiapoptotic and immunomodulatory molecules from the injected cells. This review covers past and state-of-the-art strategies in cell-based heart regeneration, highlighting the advantages, challenges, and limitations of each approach. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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