Mesenchymal Stromal Cells; Role in Tissue Repair, Drug Discovery and Immune Modulation

English, Karen; Mahon, Bernard P.; Wood, Kathryn J.

doi:10.2174/1567201810999131125222440

Cited by 29 publications

(23 citation statements)

References 168 publications

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“…Conversely, it has been proposed that MSCs mediate repair through cell education and trophic manipulation of the microenvironment [9,[32][33][34]. Given the heterogeneity of in vitro cultured MSCs, the concepts of regeneration and trophic repair may not be mutually exclusive [33,35]. In this study, MSC CM was shown to have dynamic effects pertaining to fibrotic therapy, encouraging the migration and proliferation of alveolar epithelial cells while suppressing the activation and proliferation of pulmonary fibroblasts.…”

Section: Discussionmentioning

confidence: 83%

Hepatocyte Growth Factor Is Required for Mesenchymal Stromal Cell Protection Against Bleomycin-Induced Pulmonary Fibrosis

Cahill

Kennelly

Carty

et al. 2016

Stem Cells Translational Medicine

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102

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The incidence of idiopathic pulmonary fibrosis is on the rise and existing treatments have failed to halt or reverse disease progression. Mesenchymal stromal cells (MSCs) have potent cytoprotective effects, can promote tissue repair, and have demonstrated efficacy in a range of fibrotic lung diseases; however, the exact mechanisms of action remain to be elucidated. Chemical antagonists and short hairpin RNA knockdown were used to identify the mechanisms of action used by MSCs in promoting wound healing, proliferation, and inhibiting apoptosis. Using the bleomycin induced fibrosis model, the protective effects of early or late MSC administration were examined. The role for hepatocyte growth factor (HGF) in MSC protection against bleomycin lung injury was examined using HGF knockdown MSC. Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling assay was performed on ex vivo lung sections to examine the effects of MSC on apoptosis. MSC conditioned media (CM) enhanced wound closure and inhibited apoptosis of pulmonary cells in vitro. HGF was required for MSC CM enhancement of epithelial cell proliferation and inhibition of apoptosis. In contrast, MSC required COX-2 for CM to inhibit fibroblast proliferation. In a murine model, early administration of MSC protected against bleomycin induced lung fibrosis and correlated with reduced levels of the proinflammatory cytokine interleukin-1b, reduced levels of apoptosis, and significantly increased levels of HGF. These protective effects were in part mediated by MSC derived HGF as HGF knockdown MSC were unable to protect against fibrosis in vivo. These findings delineate the mechanisms of MSC protection in a preclinical model of fibrotic lung disease. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1307-1318 SIGNIFICANCEThe mechanisms used by mesenchymal stromal cells (MSCs) in mediating protective effects in chronic models of lung disease are not understood and remain to be elucidated. These findings from in vitro studies highlight an important role for the MSC-derived soluble factors hepatocyte growth factor (HGF) and prostaglandin E 2 in promoting wound healing and inhibiting apoptosis. Furthermore, this study translates these findings demonstrating an important role for HGF in the protective effects mediated by MSC in vivo in the bleomycin model. These findings support a targeted approach to enhancing MSC therapy for fibrotic disease and highlight the importance of timing of MSC therapy.

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Section: Discussionmentioning

confidence: 83%

Hepatocyte Growth Factor Is Required for Mesenchymal Stromal Cell Protection Against Bleomycin-Induced Pulmonary Fibrosis

Cahill

Kennelly

Carty

et al. 2016

Stem Cells Translational Medicine

Self Cite

102

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“…MIAMI cells and other MSC populations play a critical role in endogenous tissue repair in vivo because they secrete abundant cytokines and growth factors [ 33 , 45 ]. To produce these reparative effects, MSCs must home to, or migrate towards, the site of tissue damage [ 33 , 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Progerin expression disrupts critical adult stem cell functions involved in tissue repair

Pacheco

Gomez

Dias

et al. 2014

Aging

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Vascular disease is one of the leading causes of death worldwide. Vascular repair, essential for tissue maintenance, is critically reduced during vascular disease and aging. Efficient vascular repair requires functional adult stem cells unimpaired by aging or mutation.One protein candidate for reducing stem cell–mediated vascular repair is progerin, an alternative splice variant of lamin A. Progerin results from erroneous activation of cryptic splice sites within the LMNA gene, and significantly increases during aging. Mutations triggering progerin overexpression cause the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS), in which patients die at approximately 13-years of age due to atherosclerosis-induced disease. Progerin expression affects tissues rich in cells that can be derived from marrow stromal cells (MSCs). Studies using various MSC subpopulations and models have led to discrepant results.Using a well-defined, immature subpopulation of MSCs, Marrow Isolated Adult Multilineage Inducible (MIAMI) cells, we find progerin significantly disrupts expression and localization of self-renewal markers, proliferation, migration, and membrane elasticity. One potential treatment, farnesyltransferase inhibitor, ameliorates some of these effects. Our results confirm proposed progerin-induced mechanisms and suggest novel ways in which progerin disturbs critical stem cell functions collectively required for proper tissue repair, offering promising treatment targets for future therapies.

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“…The development of antigen search methods targeting the interstitial tissue of cancer is currently in progress [28]. By targeting the stromal tissue of cancer, migration of the drug to the cancer tissue can be reduced.…”

Section: Techniques For Analyzing Cancer Stromal Tissues Of Model Animentioning

confidence: 99%

Search for drug discovery targets focusing on cancer stroma

Kamada

2019

Translational and Regulatory Sciences

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In recent years, it has become clear that the interstitial tissue structure varies markedly between the normal healthy state and various disease states. Focusing on differences in interstitial structure is expected to lead to the discovery of new targets for drugs. Considerable attention is currently focused on approaches that utilize organoids. The organoids retain the structure of the tissue, thereby facilitating identification of drugs that target interstitial tissues including neovascular vessels. Furthermore, protein expression analysis techniques have been developed that focus on the tissue structure based on an approach using chemical proteomics. In this mini-review, we will summarize the latest technological innovations aimed at identifying target molecules that are useful for the development of biopharmaceuticals, including antibody drugs.

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Mesenchymal Stromal Cells; Role in Tissue Repair, Drug Discovery and Immune Modulation

Cited by 29 publications

References 168 publications

Hepatocyte Growth Factor Is Required for Mesenchymal Stromal Cell Protection Against Bleomycin-Induced Pulmonary Fibrosis

Hepatocyte Growth Factor Is Required for Mesenchymal Stromal Cell Protection Against Bleomycin-Induced Pulmonary Fibrosis

Progerin expression disrupts critical adult stem cell functions involved in tissue repair

Search for drug discovery targets focusing on cancer stroma

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