scholarly journals Myh11+ microvascular mural cells and derived mesenchymal stem cells promote retinal fibrosis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
H. Clifton Ray ◽  
Bruce A. Corliss ◽  
Anthony C. Bruce ◽  
Sam Kesting ◽  
Paromita Dey ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Scar Tissue ◽  
Lineage Tracing ◽  
Ocular Injury ◽  
Myofibroblast Differentiation ◽  
Subsequent Formation ◽  
Mural Cells ◽  
Collagen Secretion ◽  
Retinal Microvasculature

Abstract Retinal diseases are frequently characterized by the accumulation of excessive scar tissue found throughout the neural retina. However, the pathophysiology of retinal fibrosis remains poorly understood, and the cell types that contribute to the fibrotic response are incompletely defined. Here, we show that myofibroblast differentiation of mural cells contributes directly to retinal fibrosis. Using lineage tracing technology, we demonstrate that after chemical ocular injury, Myh11+ mural cells detach from the retinal microvasculature and differentiate into myofibroblasts to form an epiretinal membrane. Inhibition of TGFβR attenuates Myh11+ retinal mural cell myofibroblast differentiation, and diminishes the subsequent formation of scar tissue on the surface of the retina. We demonstrate retinal fibrosis within a murine model of oxygen-induced retinopathy resulting from the intravitreal injection of adipose Myh11-derived mesenchymal stem cells, with ensuing myofibroblast differentiation. In this model, inhibiting TGFβR signaling does not significantly alter myofibroblast differentiation and collagen secretion within the retina. This work shows the complexity of retinal fibrosis, where scar formation is regulated both by TGFβR and non-TGFβR dependent processes involving mural cells and derived mesenchymal stem cells. It also offers a cautionary note on the potential deleterious, pro-fibrotic effects of exogenous MSCs once intravitreally injected into clinical patients.

Abstract MP123: The Fate and Role of Pericytes in Repair and Remodeling of the Infarcted Heart

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Linda Alex ◽  
Ya Su ◽  
Nikolaos G Frangogiannis
Keyword(s):  
Lineage Tracing ◽  
Mrna Levels ◽  
Infarct Zone ◽  
Subsequent Formation ◽  
Mural Cells ◽  
Infarcted Heart ◽  
Reporter Mice ◽  
Ng2 Cells ◽  
Migratory Phenotype

Repair of the infarcted heart is dependent on inflammation-driven activation of myofibroblasts (MFs) and subsequent formation of a scar. Though pericytes have been implicated in injury-associated fibroblast activation in several organs, their potential role in cardiac repair and fibrosis has not been studied. We hypothesized that myocardial infarction (MI) may induce pericyte activation, contributing to repair through pericyte to MF conversion, secretion of fibrogenic mediators, or regulation of angiogenesis. In order to test the hypothesis, we generated pericyte/fibroblast reporter mice (NG2 DsRed ;PDGFRα GFP ). In normal myocardium, NG2 labeled peri-endothelial mural cells that coexpressed PDGFRβ, whereas PDGFRα identified interstitial cells with fibroblast characteristics. Pericytes and fibroblasts had distinct transcriptomic profiles: NG2+/PDGFRα- pericytes expressed αSMA and low amounts of extracellular matrix (ECM) genes, whereas PDGFRα+/NG2- fibroblasts synthesized collagens. Pericyte rarefaction was noted in the necrotic core 3 days after non-reperfused MI. 3-7 days post MI, expansion of the NG2+ population in the infarct zone was associated with emergence of non-mural NG2+/αSMA+ cells with MF characteristics. FACS-sorted NG2+/PDGFRα- cells from 7-day infarcts expressed higher levels of ColIα2 (7.2±1.0-fold) and ColIIIα1 (8.9±1.14-fold), when compared to NG2+/PDGFRα- cells from normal hearts. NG2+ cells had high mRNA levels of integrins α1, αV, β1, and β5, and of MMP14, reflecting an activated migratory phenotype. To examine whether expression of ECM genes by infarct pericytes is due to fibroblast conversion, we did lineage tracing studies using NG2CreER TM ;Rosa tdTomato mice bred with the PDGFRα GFP line for reliable fibroblast identification. 7 days post MI, 5.7%±1.04 of PDGFRα+ fibroblasts were derived from NG2+ cells. Also, αSMA staining showed that 10.49%±2.73 of infarct MFs were derived from NG2+ lineage. The majority of mural cells wrapping neovessels were derived from NG2+ cells, suggesting a role for resident pericytes in infarct angiogenesis. In conclusion, upon MI, pericytes become activated and contribute to repair by undergoing conversion to a subset of myofibroblasts and by coating infarct neovessels.

Expression analysis of microRNAs and mRNAs in myofibroblast differentiation of lung resident mesenchymal stem cells

2020 ◽  
Vol 112 ◽  
pp. 10-16
Author(s):  
Cong Wang ◽  
Honghui Cao ◽  
Shen Gu ◽  
Chaowen Shi ◽  
Xiang Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Expression Analysis ◽  
Myofibroblast Differentiation

scholarly journals Perivascular-Derived Mesenchymal Stem Cells

2019 ◽  
Vol 98 (10) ◽  
pp. 1066-1072 ◽  
Author(s):  
V. Yianni ◽  
P.T. Sharpe
Keyword(s):  
Tissue Engineering ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Dental Pulp ◽  
Molecular Mechanisms ◽  
Lineage Tracing ◽  
Specific Gene ◽  
Genetic Lineage ◽  
Differentiation Potential

Cells have been identified in postnatal tissues that, when isolated from multiple mesenchymal compartments, can be stimulated in vitro to give rise to cells that resemble mature mesenchymal phenotypes, such as odontoblasts, osteoblasts, adipocytes, and myoblasts. This has made these adult cells, collectively called mesenchymal stem cells (MSCs), strong candidates for fields such as tissue engineering and regenerative medicine. Based on evidence from in vivo genetic lineage–tracing studies, pericytes have been identified as a source of MSC precursors in vivo in multiple organs, in response to injury or during homeostasis. Questions of intense debate and interest in the field of tissue engineering and regenerative studies include the following: 1) Are all pericytes, irrespective of tissue of isolation, equal in their differentiation potential? 2) What are the mechanisms that regulate the differentiation of MSCs? To gain a better understanding of the latter, recent work has utilized ChIP-seq (chromatin immunoprecipitation followed by sequencing) to reconstruct histone landscapes. This indicated that for dental pulp pericytes, the odontoblast-specific gene Dspp was found in a transcriptionally permissive state, while in bone marrow pericytes, the osteoblast-specific gene Runx2 was primed for expression. RNA sequencing has also been utilized to further characterize the 2 pericyte populations, and results highlighted that dental pulp pericytes are already precommitted to an odontoblast fate based on enrichment analysis indicating overrepresentation of key odontogenic genes. Furthermore, ChIP-seq analysis of the polycomb repressive complex 1 component RING1B indicated that this complex is likely to be involved in inhibiting inappropriate differentiation, as it localized to a number of loci of key transcription factors that are needed for the induction of adipogenesis, chondrogenesis, or myogenesis. In this review, we highlight recent data elucidating molecular mechanisms that indicate that pericytes can be tissue-specific precommitted MSC precursors in vivo and that this precommitment is a major driving force behind MSC differentiation.

scholarly journals Reversible Modulation of Myofibroblast Differentiation in Adipose-Derived Mesenchymal Stem Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (1) ◽  
pp. e86865 ◽  
Author(s):  
Vivek D. Desai ◽  
Henry C. Hsia ◽  
Jean E. Schwarzbauer
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Myofibroblast Differentiation

scholarly journals Origin of Myofibroblasts in Lung Fibrosis

2020 ◽  
Vol 1 (4) ◽  
pp. 155-162
Author(s):  
CF Hung
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Epithelial Cells ◽  
Lung Fibrosis ◽  
Cell Types ◽  
Mesenchymal Cells ◽  
Lineage Tracing ◽  
Alveolar Epithelial Cells ◽  
Multiple Sources ◽  
Alveolar Epithelial

Abstract Purpose of Review In this brief review, we will highlight important observational and experimental data in the literature that address the origin of scar-forming cells in lung fibrosis. Recent Findings Several cellular sources of activated scar-forming cells (myofibroblasts) have been postulated including alveolar epithelial cells; circulating fibrocytes; and lung stromal cell subpopulations including resident fibroblasts, pericytes, and resident mesenchymal stem cells. Recent advances in lineage-tracing models, however, fail to provide experimental evidence for epithelial and fibrocyte origins of lung myofibroblasts. Resident mesenchymal cells of the lung, which include various cell types including resident fibroblasts, pericytes, and resident mesenchymal stem cells, appear to be important sources of myofibroblasts in murine models of lung injury and fibrosis. Summary Lung myofibroblasts likely originate from multiple sources of lung-resident mesenchymal cells. Their relative contributions may vary depending on the type of injury. Although lineage-tracing experiments have failed to show significant contribution from epithelial cells or fibrocytes, they may play important functional roles in myofibroblast activation through paracrine signaling.

scholarly journals Effects of Intravitreal Injection of Hypoxia-Induced Umbilical Cord Mesenchymal Stem Cell Exosomes On Diabetic Retinopathy

2021 ◽  
Author(s):  
Yan Fu ◽  
Zhao-Hui Gu ◽  
Yue-Ling Zhang ◽  
Xiao-Ying Wen ◽  
Na Yang
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Diabetic Retinopathy ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Intravitreal Injection ◽  
Umbilical Cord ◽  
Diabetic Rats ◽  
Human Umbilical Cord ◽  
Retinal Microvasculature

Abstract Diabetic retinopathy (DR) is a highly specific condition affecting the microvasculature that is the leading cause of visual impairment in working-age people in developed countries. The ability of intravitreal administration of mesenchymal stem cells (MSCs) to repair the retinal vasculature and neurons of the inner retina in DR has been explored. It was recently revealed that exosomes are primarily responsible for the therapeutic effects of MSCs; therefore, intravitreal injection of these vesicles appears to be a better option for treatment of retinal injury, and there is evidence that hypoxic conditions can promote exosome release from MSCs. Here we investigated the effect of intravitreal injection of hypoxia-induced human umbilical cord mesenchymal stem cell exosomes (hypo-hucMSC-Exs) on the retinal microvasculature in rats with DR. We also assessed whether hypo-hucMSC-Exs exhibited greater effects on DR than exosomes from human umbilical cord mesenchymal stem cells not exposed to hypoxia (hucMSC-Exs). Exosomes were isolated from MSCs cultured under normoxic and hypoxic culture conditions. Transmission electron microscope, nanoparticle tracking, and western blot analyses were applied to characterize hucMSC-Exs. Streptozotocin (STZ)-induced diabetic rats were used as a model for DR. Fundus fluorescein angiography (FFA) was conducted to evaluate retinal microvasculature changes in vivo at 4, 8, and 12 weeks following intravitreal injection of exosomes. No significant changes were observed in the control rats without DR receiving intravitreal phosphate-buffered saline (PBS) injection throughout the study. Control model rats receiving PBS injections developed DR characterized by retinal microvascular changes, including tortuous vessels, massive microaneurysms, and late leakage of fluorescein dye was, which were visualized using FFA. These changes were ameliorated in diabetic rats treated with hucMSC-Exs. Further, injection of hypo-hucMSC-Exs remarkably reduced the extent of microvasculature lesions compared with hucMSC-Exs. These findings suggest that intravitreal injection of hucMSC-Exs can prevent diabetes-induced microvasculature lesions and that hypo-hucMSC-Exs can enhance this effect and have potential for application in DR prevention and treatment.

scholarly journals Exosomes derived from human umbilical cord blood mesenchymal stem cells stimulate regenerative wound healing via transforming growth factor-β receptor inhibition

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yan Zhang ◽  
Yingjin Pan ◽  
Yanhong Liu ◽  
Xiheng Li ◽  
Liang Tang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Scar Formation ◽  
Myofibroblast Differentiation ◽  
Receptor Inhibition ◽  
Β Receptor

Abstract Background Scar formation is a common consequence of skin wound healing, and no effective treatment exists. Umbilical cord blood mesenchymal stem cells (UCB-MSCs) can improve wound healing; however, the role of UCB-MSCs remains unclear and whether they can ameliorate scar formation has not been fully elucidated. Methods To determine the function of UCB-MSCs, we examined and compared the therapeutic effects of UCB-MSCs and UCB-MSC-derived exosomes (UCB-MSC-exo) on skin healing in rats. Moreover, UCB-MSC-exo-specific miRNAs were identified and their effects in inhibiting the human dermal fibroblast (HDF) differentiation into myofibroblasts were investigated. Results Both UCB-MSCs and UCB-MSC-exo accelerated wound closure; reduced scar formation; improved the regeneration of skin appendages, nerves, and vessels; and regulated the natural distribution of collagen fibers in wound healing. Additionally, UCB-MSC-exo suppressed the excessive formation of myofibroblasts and collagen I and increased the proliferation and migration of skin cells in vivo and in vitro. Functional analysis showed that UCB-MSC-derived miRNAs were closely related to the transforming growth factor-β (TGF-β) signaling pathway, which could induce myofibroblast differentiation. We identified abundant miRNAs that were highly expressed in UCB-MSC-exo. miR-21-5p and miR-125b-5p were predicted to contribute to TGF-β receptor type II (TGFBR2) and TGF-β receptor type I (TGFBR1) inhibition, respectively. Using miRNA mimics, we found that miR-21-5p and miR-125b-5p were critical for anti-myofibroblast differentiation in the TGF-β1-induced HDF. Conclusion The effect of UCB-MSCs in stimulating regenerative wound healing might be achieved through exosomes, which can be, in part, through miR-21-5p- and miR-125b-5p-mediated TGF-β receptor inhibition, suggesting that UCB-MSC-exo might represent a novel strategy to prevent scar formation during wound healing.

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