Expanding the Paracrine Hypothesis of Stem Cell–Mediated Repair in the Heart

Glembotski, Christopher C.

doi:10.1161/circresaha.116.310298

Cited by 24 publications

(21 citation statements)

References 15 publications

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“…Exosome-based mechanisms of stem cell-mediated benefit have recently attracted considerable attention. Glembotski recently phrased this as follows: "The exosomecentric view drives much of the current thinking of those who study of stem cell-mediated repair in the heart" (11).…”

mentioning

confidence: 99%

Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia

Barile¹,

Milano²,

Vassalli³

2017

Stem Cell Investig.

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When injected into acutely infarcted rodent or pig hearts, naturally secreted nanovesicles known as exosomes from cardiac-derived progenitor cells (CPCs) reduce scar size and improve cardiac function. In this regard, exosomes fully mimic the benefits of injecting their parent cells. This recognition paves the way to the development of exosome-based, cell-free treatments for heart disease that could possibly supplant cellbased therapies. Mechanisms of benefit of these vesicles are incompletely understood but cytoprotection, stimulation of angiogenesis, induction of antifibrotic cardiac fibroblasts, and modulation of M1/M2 polarization of macrophages infiltrating the infarcted region can all play important roles. Accordingly, the beneficial molecules carried by CPC-secreted exosomes have been identified only in part but cytoprotective and proangiogenic microRNAs (miRNA) and proteins have been described. Besides CPC-secreted exosomes, vesicles released from other cell types including mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iSPCs) have also been associated with cardioprotection. This review aims to discuss recent advances in our understanding of the role of secreted vesicles in cardiac repair, with a focus on CPC-derived exosomes.

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mentioning

confidence: 99%

Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia

Barile¹,

Milano²,

Vassalli³

2017

Stem Cell Investig.

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“…Soluble ER proteins, which include secreted and ER-resident proteins, and membrane proteins are made on ER-bound ribosomes, where they are co-translationally translocated through an ER membrane channel, the translocon, across the ER membrane into the lumen of the ER, or they are embedded in the ER membrane (Lingappa and Blobel, 1980;Kelly, 1985;Nicchitta, 2002;Egea et al, 2005;Viotti, 2016;Glembotski, 2017). This is followed by continued folding of the nascent proteins, as well as post-translational modifications, such as glycosylation, phosphorylation, disulfide bond formation, and proteolytic processing, most of which also affect the folding process and take place en route to their final destinations (Braakman and Bulleid, 2011;Steiner, 2011).…”

Section: Er Stress and The Unfolded Protein Responsementioning

confidence: 99%

ATF6 as a Nodal Regulator of Proteostasis in the Heart

et al. 2020

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Proteostasis encompasses a homeostatic cellular network in all cells that maintains the integrity of the proteome, which is critical for optimal cellular function. The components of the proteostasis network include protein synthesis, folding, trafficking, and degradation. Cardiac myocytes have a specialized endoplasmic reticulum (ER) called the sarcoplasmic reticulum that is well known for its role in contractile calcium handling. However, less studied is the proteostasis network associated with the ER, which is of particular importance in cardiac myocytes because it ensures the integrity of proteins that are critical for cardiac contraction, e.g., ion channels, as well as proteins necessary for maintaining myocyte viability and interaction with other cell types, e.g., secreted hormones and growth factors. A major aspect of the ER proteostasis network is the ER unfolded protein response (UPR), which is initiated when misfolded proteins in the ER activate a group of three ER transmembrane proteins, one of which is the transcription factor, ATF6. Prior to studies in the heart, ATF6 had been shown in model cell lines to be primarily adaptive, exerting protective effects by inducing genes that encode ER proteins that fortify protein-folding in this organelle, thus establishing the canonical role for ATF6. Subsequent studies in isolated cardiac myocytes and in the myocardium, in vivo, have expanded roles for ATF6 beyond the canonical functions to include the induction of genes that encode proteins outside of the ER that do not have known functions that are obviously related to ER protein-folding. The identification of such non-canonical roles for ATF6, as well as findings that the gene programs induced by ATF6 differ depending on the stimulus, have piqued interest in further research on ATF6 as an adaptive effector in cardiac myocytes, underscoring the therapeutic potential of activating ATF6 in the heart. Moreover, discoveries of small molecule activators of ATF6 that adaptively affect the heart, as well as other organs, in vivo, have expanded the potential for development of ATF6-based therapeutics. This review focuses on the ATF6 arm of the ER UPR and its effects on the proteostasis network in the myocardium.

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“…Exosomes are membrane-bounded vesicles that comprise a subset of the extracellular vesicles (EVs) secreted via the fusion of multivescicular bodies (MVBs) with the plasma membrane by almost every cell in the body [77]. They are approximately 70 to 150nm in size, are crucial for cellular communication, and help to orient the cell spatially and temporally [78].…”

Section: Exosomes As Potential Candidates To Stimulate Endogenous Carmentioning

confidence: 99%

Non-invasive strategies for stimulating endogenous repair and regenerative mechanisms in the damaged heart

Lewis

Kumar

Ellison

2018

Pharmacological Research

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The adult myocardium, including human, harbours a population of resident multi-potent cardiac stem cells (CSCs), which when stimulated under the right conditions can give rise to new cardiomyocytes and vasculature. Elucidation of the cellular and molecular mechanisms that govern CSC biology and their role in myocardial regeneration will allow the design and development of optimal therapeutic interventions. It is now evident that different growth factors and cytokines govern CSC survival, proliferation, migration and differentiation, as well as playing a role in activating cardiac repair mechanisms such as improving angiogenesis, cardiomyocyte survival and limiting fibrosis. This review article will summarize the evidence for a role of VEGF, NRG-1, IGF-1, HGF, EGF, FGF and TGF-β1 in modulating the repair and regeneration of cardiac tissue. It will also discuss the use of exosomes and exercise training as interventions to stimulate the endogenous repair and regenerative mechanisms in the damaged heart.

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Expanding the Paracrine Hypothesis of Stem Cell–Mediated Repair in the Heart

Cited by 24 publications

References 15 publications

Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia

Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia

ATF6 as a Nodal Regulator of Proteostasis in the Heart

Non-invasive strategies for stimulating endogenous repair and regenerative mechanisms in the damaged heart

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