scholarly journals Shear Stress Induces Differentiation of Endothelial Lineage Cells to Protect Neonatal Brain from Hypoxic-Ischemic Injury through NRP1 and VEGFR2 Signaling

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Chia-Wei Huang ◽  
Chao-Ching Huang ◽  
Yuh-Ling Chen ◽  
Shih-Chen Fan ◽  
Yuan-Yu Hsueh ◽  
...  
Keyword(s):  
Shear Stress ◽  
Brain Injuries ◽  
Therapeutic Potential ◽  
Growth Factor Receptor ◽  
Stem Cell Differentiation ◽  
Cell Based Therapy ◽  
Neuropilin 1 ◽  
Endothelial Lineage ◽  
Endothelial Growth Medium

Neonatal hypoxic-ischemic (HI) brain injuries disrupt the integrity of neurovascular structure and lead to lifelong neurological deficit. The devastating damage can be ameliorated by preserving the endothelial network, but the source for therapeutic cells is limited. We aim to evaluate the beneficial effect of mechanical shear stress in the differentiation of endothelial lineage cells (ELCs) from adipose-derived stem cells (ASCs) and the possible intracellular signals to protect HI injury using cell-based therapy in the neonatal rats. The ASCs expressed early endothelial markers after biochemical stimulation of endothelial growth medium. The ELCs with full endothelial characteristics were accomplished after a subsequential shear stress application for 24 hours. When comparing the therapeutic potential of ASCs and ELCs, the ELCs treatment significantly reduced the infarction area and preserved neurovascular architecture in HI injured brain. The transplanted ELCs can migrate and engraft into the brain tissue, especially in vessels, where they promoted the angiogenesis. The activation of Akt by neuropilin 1 (NRP1) and vascular endothelial growth factor receptor 2 (VEGFR2) was important for ELC migration and followingin vivotherapeutic outcomes. Therefore, the current study demonstrated importance of mechanical factor in stem cell differentiation and showed promising protection of brain from HI injury using ELCs treatment.

scholarly journals The Anti-fibrotic Effect of Human Fetal Skin-derived Stem Cell Secretome on the Liver Fibrosis

2020 ◽  
Author(s):  
Xia Yao ◽  
Jing Wang ◽  
Jiajing Zhu ◽  
Xiaoli Rong
Keyword(s):  
Stem Cells ◽  
Liver Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Fetal Skin ◽  
Mesenchymal Transition ◽  
Cell Based Therapy ◽  
Causes Of Mortality ◽  
Smad7 Expression

Abstract Background: Liver fibrosis resulting from chronic liver injury is one of the major causes of mortality worldwide. Stem cells-secreted secretome has been evaluated for overcoming the limitations of cell-based therapy in hepatic disease, while maintaining its advantages.Methods: In this study, we investigated the effect ofhuman fetal skin-derived stem cells (hFFSCs) secretome in the treatment of liver fibrosis. To determine the therapeutic potential of the hFFSCssecretome in liver fibrosis, we established the CCl4-induced rat liver fibrosis model, and administered hFFSCssecretome in vivo. Moreover, we investigated the anti-fibrotic mechanism of hFFSCssecretome in hepatic stellate cells (HSCs).Results: Our results showed that hFFSCssecretomeffectively reduced collagen content in liver, improved the liver function and promoted liver regeneration. Interestingly, we also found thathFFSCssecretom reduced liver fibrosis through suppressing the epithelial-mesenchymal transition (EMT) process. In addition, we found that hFSSCsecretom inhibited the TGF-β1, Smad2, Smad3, and Collagen I expression, however, increased Smad7 expression.Conclusions: In conclusions, our results suggest that hFFSCssecretome treatment could reduce CCl4-induced liver fibrosis via regulating the TGF-β/Smad signal pathway.

scholarly journals Increased Mesenchymal Stem Cell Functionalization in Three-Dimensional Manufacturing Settings for Enhanced Therapeutic Applications

2021 ◽  
Vol 9 ◽  
Author(s):  
Dimitrios Kouroupis ◽  
Diego Correa
Keyword(s):  
Therapeutic Potential ◽  
Ex Vivo ◽  
Three Dimensional ◽  
Therapeutic Applications ◽  
Cell Based Therapy ◽  
Donor Variability ◽  
Healing Bone ◽  
Preclinical Animal Models

Mesenchymal stem/stromal cell (MSC) exist within their in vivo niches as part of heterogeneous cell populations, exhibiting variable stemness potential and supportive functionalities. Conventional extensive 2D in vitro MSC expansion, aimed at obtaining clinically relevant therapeutic cell numbers, results in detrimental effects on both cellular characteristics (e.g., phenotypic changes and senescence) and functions (e.g., differentiation capacity and immunomodulatory effects). These deleterious effects, added to the inherent inter-donor variability, negatively affect the standardization and reproducibility of MSC therapeutic potential. The resulting manufacturing challenges that drive the qualitative variability of MSC-based products is evident in various clinical trials where MSC therapeutic efficacy is moderate or, in some cases, totally insufficient. To circumvent these limitations, various in vitro/ex vivo techniques have been applied to manufacturing protocols to induce specific features, attributes, and functions in expanding cells. Exposure to inflammatory cues (cell priming) is one of them, however, with untoward effects such as transient expression of HLA-DR preventing allogeneic therapeutic schemes. MSC functionalization can be also achieved by in vitro 3D culturing techniques, in an effort to more closely recapitulate the in vivo MSC niche. The resulting spheroid structures provide spatial cell organization with increased cell–cell interactions, stable, or even enhanced phenotypic profiles, and increased trophic and immunomodulatory functionalities. In that context, MSC 3D spheroids have shown enhanced “medicinal signaling” activities and increased homing and survival capacities upon transplantation in vivo. Importantly, MSC spheroids have been applied in various preclinical animal models including wound healing, bone and osteochondral defects, and cardiovascular diseases showing safety and efficacy in vivo. Therefore, the incorporation of 3D MSC culturing approach into cell-based therapy would significantly impact the field, as more reproducible clinical outcomes may be achieved without requiring ex vivo stimulatory regimes. In the present review, we discuss the MSC functionalization in 3D settings and how this strategy can contribute to an improved MSC-based product for safer and more effective therapeutic applications.

Human fetal skin-derived stem cell secretome reduce liver fibrosis

2020 ◽  
Author(s):  
Xia Yao ◽  
Jing Wang ◽  
Jiajing Zhu ◽  
Xiaoli Rong
Keyword(s):  
Stem Cells ◽  
Liver Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Fetal Skin ◽  
Mesenchymal Transition ◽  
Cell Based Therapy ◽  
Current Therapies ◽  
Causes Of Mortality

Abstract Background: Liver fibrosis resulting from a chronic liver injury is one of the significant causes of mortality. Stem cells-secreted secretome has been evaluated for overcoming the limitations of cell-based therapy in hepatic disease while maintaining its advantages over the current therapies. Methods: In this study, we investigated the effect of human fetal skin-derived stem cells (hFSSCs) secretome in the treatment of liver fibrosis. To determine the therapeutic potential of the hFSSCs secretome in liver fibrosis, we established the CCl4-induced liver fibrosis rat model, and we administered hFSSCs secretome in vivo. Moreover, we investigated the anti-fibrotic mechanism of hFSSCs secretome in hepatic stellate cells (HSCs). Results: Our results showed that hFSSCs secretome effectively reduced collagen content in the liver, and improved the liver function and promoted liver regeneration. Interestingly, we also found that hFSSCs secretome reduced liver fibrosis through suppressing the epithelial-mesenchymal transition (EMT) process. In addition, we found that hFSSC secretome inhibited the TGF-β1, Smad2, Smad3, and Collagen I expression, while we observed, increased Smad7 expression. Conclusions: In conclusion, our results suggest that hFSSCs secretome treatment could reduce CCl4-induced liver fibrosis via regulating the TGF-β/Smad signal pathway.

scholarly journals Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
HaoRan Tang ◽  
Leo Leung ◽  
Grazia Saturno ◽  
Amaya Viros ◽  
Duncan Smith ◽  
...  
Keyword(s):  
Cell Surface ◽  
Therapeutic Potential ◽  
Lysyl Oxidase ◽  
Tumour Progression ◽  
Growth Factor Receptor ◽  
Tumour Microenvironment ◽  
Metastatic Tumour ◽  
Egf Receptors ◽  
Molecule Inhibitor

Abstract Lysyl oxidase (LOX) remodels the tumour microenvironment by cross-linking the extracellular matrix. LOX overexpression is associated with poor cancer outcomes. Here, we find that LOX regulates the epidermal growth factor receptor (EGFR) to drive tumour progression. We show that LOX regulates EGFR by suppressing TGFβ1 signalling through the secreted protease HTRA1. This increases the expression of Matrilin2 (MATN2), an EGF-like domain-containing protein that traps EGFR at the cell surface to facilitate its activation by EGF. We describe a pharmacological inhibitor of LOX, CCT365623, which disrupts EGFR cell surface retention and delays the growth of primary and metastatic tumour cells in vivo. Thus, we show that LOX regulates EGFR cell surface retention to drive tumour progression, and we validate the therapeutic potential of inhibiting this pathway with the small molecule inhibitor CCT365623.

Nanocarrier Mediated siRNA Delivery Targeting Stem Cell Differentiation

2020 ◽  
Vol 15 (2) ◽  
pp. 155-172 ◽  
Author(s):  
Fiona Fernandes ◽  
Pooja Kotharkar ◽  
Adrija Chakravorty ◽  
Meenal Kowshik ◽  
Indrani Talukdar
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Viral Vectors ◽  
Therapeutic Potential ◽  
Transfection Efficiency ◽  
Polymeric Nanoparticles ◽  
Sirna Delivery ◽  
Stem Cell Differentiation

Stem cell-based regenerative medicine holds exceptional therapeutic potential and hence the development of efficient techniques to enhance control over the rate of differentiation has been the focus of active research. One of the strategies to achieve this involves delivering siRNA into stem cells and exploiting the RNA interference (RNAi) mechanism. Transport of siRNA across the cell membrane is a challenge due to its anionic property, especially in primary human cells and stem cells. Moreover, naked siRNA incites immune responses, may cause off-target effects, exhibits low stability and is easily degraded by endonucleases in the bloodstream. Although siRNA delivery using viral vectors and electroporation has been used in stem cells, these methods demonstrate low transfection efficiency, cytotoxicity, immunogenicity, events of integration and may involve laborious customization. With the advent of nanotechnology, nanocarriers which act as novel gene delivery vehicles designed to overcome the problems associated with safety and practicality are being developed. The various nanomaterials that are currently being explored and discussed in this review include liposomes, carbon nanotubes, quantum dots, protein and peptide nanocarriers, magnetic nanoparticles, polymeric nanoparticles, etc. These nanodelivery agents exhibit advantages such as low immunogenic response, biocompatibility, design flexibility allowing for surface modification and functionalization, and control over the surface topography for achieving the desired rate of siRNA delivery and improved gene knockdown efficiency. This review also includes discussion on siRNA co-delivery with imaging agents, plasmid DNA, drugs etc. to achieve combined diagnostic and enhanced therapeutic functionality, both for in vitro and in vivo applications.

Bio-mimicking Shear Stress Environments for Enhancing Mesenchymal Stem Cell Differentiation

2020 ◽  
Vol 15 (5) ◽  
pp. 414-427
Author(s):  
Seep Arora ◽  
Akshaya Srinivasan ◽  
Chak Ming Leung ◽  
Yi-Chin Toh
Keyword(s):  
Stem Cells ◽  
Shear Stress ◽  
Stem Cell ◽  
Stem Cell Differentiation ◽  
In Vitro Differentiation ◽  
Msc Differentiation ◽  
Biophysical Cues

Mesenchymal stem cells (MSCs) are multipotent stromal cells, with the ability to differentiate into mesodermal (e.g., adipocyte, chondrocyte, hematopoietic, myocyte, osteoblast), ectodermal (e.g., epithelial, neural) and endodermal (e.g., hepatocyte, islet cell) lineages based on the type of induction cues provided. As compared to embryonic stem cells, MSCs hold a multitude of advantages from a clinical translation perspective, including ease of isolation, low immunogenicity and limited ethical concerns. Therefore, MSCs are a promising stem cell source for different regenerative medicine applications. The in vitro differentiation of MSCs into different lineages relies on effective mimicking of the in vivo milieu, including both biochemical and mechanical stimuli. As compared to other biophysical cues, such as substrate stiffness and topography, the role of fluid shear stress (SS) in regulating MSC differentiation has been investigated to a lesser extent although the role of interstitial fluid and vascular flow in regulating the normal physiology of bone, muscle and cardiovascular tissues is well-known. This review aims to summarise the current state-of-the-art regarding the role of SS in the differentiation of MSCs into osteogenic, cardiovascular, chondrogenic, adipogenic and neurogenic lineages. We will also highlight and discuss the potential of employing SS to augment the differentiation of MSCs to other lineages, where SS is known to play a role physiologically but has not yet been successfully harnessed for in vitro differentiation, including liver, kidney and corneal tissue lineage cells. The incorporation of SS, in combination with biochemical and biophysical cues during MSC differentiation, may provide a promising avenue to improve the functionality of the differentiated cells by more closely mimicking the in vivo milieu.

scholarly journals A chemically unmodified agonistic DNA with growth factor functionality for in vivo therapeutic application

2020 ◽  
Vol 6 (14) ◽  
pp. eaay2801 ◽  
Author(s):  
Ryosuke Ueki ◽  
Satoshi Uchida ◽  
Naoto Kanda ◽  
Naoki Yamada ◽  
Ayaka Ueki ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Therapeutic Potential ◽  
Growth Factor Receptor ◽  
Liver Parenchyma ◽  
Therapeutic Effects ◽  
Target Tissue ◽  
Systemic Injection ◽  
High Production Cost

Although growth factors have great therapeutic potential because of their regenerative functions, they often have intrinsic drawbacks, such as low thermal stability and high production cost. Oligonucleotides have recently emerged as promising chemical entities for designing synthetic alternatives to growth factors. However, their applications in vivo have been recognized as a challenge because of their susceptibility to nucleases and limited distribution to a target tissue. Here, we present the first example of oligonucleotide-based growth factor mimetics that exerts therapeutic effects at a target tissue after systemic injection. The aptamer was designed to dimerize a growth factor receptor for its activation and mitigated the progression of Fas-induced fulminant hepatitis in a mouse model. This unprecedented functionality of the aptamer can be reasonably explained by its high nuclease stability and migration to the liver parenchyma. These mechanistic analyses provided insights for the successful application of aptamer-based receptor agonists.

scholarly journals Detection and Monitoring of Regulatory Immune Cells Following Their Adoptive Transfer in Organ Transplantation

2020 ◽  
Vol 11 ◽  
Author(s):  
Lillian M. Tran ◽  
Angus W. Thomson
Keyword(s):  
Clinical Trials ◽  
Organ Transplantation ◽  
Immune Cells ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Tolerance Induction ◽  
Current Status ◽  
Transplant Tolerance ◽  
Cell Based Therapy

Application of cell-based immunotherapy in organ transplantation to minimize the burden of immunosuppressive medication and promote allograft tolerance has expanded significantly over the past decade. Adoptively transferred regulatory immune cells prolong allograft survival and transplant tolerance in pre-clinical models. Many cell products are currently under investigation in early phase human clinical trials designed to assess feasibility and safety. Despite rapid advances in manufacturing practices, defining the appropriate protocol that will optimize in vivo conditions for tolerance induction remains a major challenge and depends heavily on understanding the fate, biodistribution, functional stability and longevity of the cell product after administration. This review focuses on in vivo detection and monitoring of various regulatory immune cell types administered for allograft tolerance induction in both pre-clinical animal models and early human clinical trials. We discuss the current status of various non-invasive methods for tracking regulatory cell products in the context of organ transplantation and implications for enhanced understanding of the therapeutic potential of cell-based therapy in the broad context of control of immune-mediated inflammatory disorders.

scholarly journals Human fetal skin-derived stem cell secretome reduce liver fibrosis by regulating TGF-β/Smad signal pathway

2020 ◽  
Author(s):  
Xia Yao ◽  
Jing Wang ◽  
Jiajing Zhu ◽  
Xiaoli Rong
Keyword(s):  
Stem Cells ◽  
Liver Fibrosis ◽  
Therapeutic Potential ◽  
Signal Pathway ◽  
Fetal Skin ◽  
Cell Based Therapy ◽  
Causes Of Mortality ◽  
Smad7 Expression ◽  
Rat Liver Fibrosis

Abstract Background: Liver fibrosis resulting from chronic liver injury is one of the major causes of mortality worldwide. Stem cells-secreted secretome has been evaluated for overcoming the limitations of cell-based therapy in hepatic disease, while maintaining its advantages. Methods: In this study, we investigated the effect of human fetal skin-derived stem cells (hFFSCs) secretome in the treatment of liver fibrosis. To determine the therapeutic potential of the hFFSCs secretome in liver fibrosis, we established the CCl4-induced rat liver fibrosis model, and administered hFFSCs secretome in vivo. Moreover, we investigated the anti-fibrotic mechanism of hFFSCs secretome in hepatic stellate cells (HSCs). Results: Our results showed that hFFSCs secretom effectively reduced collagen content in liver, improved the liver function and promoted liver regeneration. In addition, we found that hFSSC secretom inhibited the TGF-β1, Smad2, Smad3, and Collagen I expression, however, increased Smad7 expression. Conclusions: In conclusions, our results suggest that hFFSCs secretome treatment could reduce CCl4-induced liver fibrosis via regulating the TGF-β/Smad signal pathway.

scholarly journals In vivo and ex vivo methods of growing a liver bud through tissue connection

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Yusuke Yanagi ◽  
Koichi Nakayama ◽  
Tomoaki Taguchi ◽  
Shin Enosawa ◽  
Tadashi Tamura ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Ex Vivo ◽  
The Novel ◽  
Orthotopic Transplantation ◽  
New Approach ◽  
Tissue Organization ◽  
Cell Based Therapy ◽  
Liver Organoids

Abstract Cell-based therapy has been proposed as an alternative to orthotopic liver transplantation. The novel transplantation of an in vitro-generated liver bud might have therapeutic potential. In vivo and ex vivo methods for growing a liver bud are essential for paving the way for the clinical translation of liver bud transplantation. We herein report a novel transplantation method for liver buds that are grown in vivo involving orthotopic transplantation on the transected parenchyma of the liver, which showed long engraftment and marked growth in comparison to heterotopic transplantation. Furthermore, this study demonstrates a method for rapidly fabricating scalable liver-like tissue by fusing hundreds of liver bud-like spheroids using a 3D bioprinter. Its system to fix the shape of the 3D tissue with the needle-array system enabled the fabrication of elaborate geometry and the immediate execution of culture circulation after 3D printing—thereby avoiding an ischemic environment ex vivo. The ex vivo-fabricated human liver-like tissue exhibited self-tissue organization ex vivo and engraftment on the liver of nude rats. These achievements conclusively show both in vivo and ex vivo methods for growing in vitro-generated liver buds. These methods provide a new approach for in vitro-generated liver organoids transplantation.

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