Cardiomyocyte-derived CXCL12 is not involved in cardiogenesis but plays a crucial role in myocardial infarction

Mühlstedt, Silke; Ghadge, Santhosh Kumar; Duchêne, Johan; Qadri, Fatimunnisa; Järve, Anne; Vilianovich, Larisa; Popova, Elena; Pohlmann, Andreas; Niendorf, Thoralf; Boyé, Philipp; Özcelik, Cemil; Bäder, Michael

doi:10.1007/s00109-016-1432-1

Cited by 18 publications

(13 citation statements)

References 48 publications

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“…From a translational perspective, IM Exo injection would hardly be feasible for treating acute MI patients, thus, improving Exo retention by the heart after IC or systemic administration is a crucial goal. Recently studies have attempted to engineer transmembrane proteins of Exo using “cardiac-homing peptide” to increase targeting capability to cardiac tissues [38,39,40]. These study showed that homing peptides displayed on the external part of Exo, although not directly implicated into mechanism of action of Exo, promote the specificity and efficiency of systemic delivery of Exo.…”

Section: Discussionmentioning

confidence: 99%

Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration

Ciullo

Biemmi

Milano

et al. 2019

IJMS

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Cell therapy has been evaluated to enhance heart function after injury. Delivered cells mostly act via paracrine mechanisms, including secreted growth factors, cytokines, and vesicles, such as exosomes (Exo). Intramyocardial injection of cardiac-resident progenitor cells (CPC)-derived Exo reduced scarring and improved cardiac function after myocardial infarction in rats. Here, we explore a clinically relevant approach to enhance the homing process to cardiomyocytes (CM), which is crucial for therapeutic efficacy upon systemic delivery of Exo. By overexpressing exosomal CXCR4, we increased the efficacy of plasmatic injection of cardioprotective Exo-CPC by increasing their bioavailability to ischemic hearts. Intravenous injection of ExoCXCR4 significantly reduced infarct size and improved left ventricle ejection fraction at 4 weeks compared to ExoCTRL (p < 0.01). Hemodynamic measurements showed that ExoCXCR4 improved dp/dt min, as compared to ExoCTRL and PBS group. In vitro, ExoCXCR4 was more bioactive than ExoCTRL in preventing CM death. This in vitro effect was independent from SDF-1α, as shown by using AMD3100 as specific CXCR4 antagonist. We showed, for the first time, that systemic administration of Exo derived from CXCR4-overexpressing CPC improves heart function in a rat model of ischemia reperfusion injury These data represent a substantial step toward clinical application of Exo-based therapeutics in cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration

Ciullo

Biemmi

Milano

et al. 2019

IJMS

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“…Old Plt-β2M -/mice did not have a significant increase in inflammatory markers ( Figure 2A). Conversely, old Plt-β2M -/mice had a significant increase in pro-reparative markers including Il10, Il27, and Cxcl12 [29] compared to young genotype control mice ( Figure 2B). While old WT mice had an increase in Il10 and Cxcl12 compared to their young genotype controls, old Plt-β2M -/had significantly more Il10 and Il27 compared to old WT mice ( Figure 2B).…”

Section: Circulating Monocytes Are Phenotypically and Functionally DImentioning

confidence: 98%

Platelet-derived β2m regulates age related monocyte/macrophage functions

Hilt

Ture

Mohan

et al. 2019

Aging

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Platelets have central roles in both immune responses and development. Stimulated platelets express leukocyte adhesion molecules and release numerous immune modulatory factors that recruit and activate leukocytes, both at the sites of activation and distantly. Monocytes are innate immune cells with dynamic immune modulatory functions that change during the aging process, a phenomenon termed "inflammaging". We have previously shown that platelets are a major source of plasma beta-2 microglobulin (β2M) and that β2M induced a monocyte pro-inflammatory phenotype. Plasma β2M increases with age and is a pro-aging factor. We hypothesized that platelet derived β2M regulates monocyte phenotypes in the context of aging. Using wild-type (WT) and platelet specific β2M knockout mice (Plt-β2M-/-) mice, we found that plasma β2M increased with age and correlated with increased circulating Ly6C Hi monocytes. However, aged Plt-β2M-/mice had significantly fewer Ly6C Hi monocytes compared to WT mice. Quantitative real-time PCR of circulating monocytes showed that WT mouse monocytes were more "pro-inflammatory" with age, while Plt-β2M-/derived monocytes adopted a "pro-reparative" phenotype. Older Plt-β2M-/mice had a significant decline in heart function compared to age matched WT mice, as well as increased cardiac fibrosis and pro-fibrotic markers. These data suggest that platelet-derived β2M regulates age associated monocyte polarization, and a loss of platelet derived β2M shifted monocytes and macrophages to a pro-reparative phenotype and increased pro-fibrotic cardiac responses. Platelet regulation of monocyte phenotypes via β2M may maintain a balance between inflammatory and reparative signals that affects age related physiologic outcomes.

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“…CD40 ligand are expressed on non-inflammatory cells in inflammatory states and induce a wide variety of immunological signaling, like T-cell induction ( Elgueta et al, 2009 ). CXCL12/SDF-1 has been described as a crucial factor for stem cell recruitment after hypoxic cardiac injury, but adverse effects on remodeling processes have also been associated with its upregulated release ( Mühlstedt et al, 2016 ). Similarly, the effect of IL-17 and its variant IL-17E in myocardial infarction has revealed contradictory data on outcome; however, a general understanding that IL-17 induces CMC apoptosis leading to iNOS and free radical release subsequently leading to leukocyte accumulation and cardiac repair at the target site ( Carreau et al, 2011 ; Pietrowski et al, 2011 ; Mora-Ruíz et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Comparative Effect of MSC Secretome to MSC Co-culture on Cardiomyocyte Gene Expression Under Hypoxic Conditions in vitro

Kastner

Mester-Tonczar

Winkler

et al. 2020

Front. Bioeng. Biotechnol.

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Introduction Despite major leaps in regenerative medicine, the regeneration of cardiomyocytes after ischemic conditions remains to elucidate. It is crucial to understand hypoxia induced cellular mechanisms to provide advanced treatment options, including the use of stem cell paracrine factors for myocardial regeneration. Materials and Methods In this study, the regenerative potential of hypoxic human cardiomyocytes (group Hyp-CMC) in vitro was evaluated when co-cultured with human bone-marrow derived MSC (group Hyp-CMC-MSC) or stimulated with the secretome of MSC (group Hyp-CMC-S MSC ). The secretome of normoxic MSC and CMC, and the hypoxic CMC was analyzed with a cytokine panel. Gene expression changes of HIF-1 α, proliferation marker Ki-67 and cytokinesis marker RhoA over different reoxygenation time periods of 4, 8, 24, 48, and 72 h were analyzed in comparison to normoxic CMC and MSC. Further, the proinflammatory cytokine IL-18 protein expression change, metabolic activity and proliferation was assessed in all experimental setups. Results and Conclusion HIF-1 α was persistently overexpressed in Hyp-CMC-S MSC as compared to Hyp-CMC (except at 72 h). Hyp-CMC-MSC showed a weaker HIF-1 α expression than Hyp-CMC-S MSC in most tested time points, except after 8 h. The Ki-67 expression showed the strongest upregulation in Hyp-CMC after 24 and 48 h incubation, then returned to baseline level, while a temporary increase in Ki-67 expression in Hyp-CMC-MSC at 4 and 8 h and at 48 h in Hyp-CMC-S MSC could be observed. RhoA was increased in normoxic MSCs and in Hyp-CMC-S MSC over time, but not in Hyp-CMC-MSC. A temporary increase in IL-18 protein expression was detected in Hyp-CMC-SMSC and Hyp-CMC. Our study demonstrates timely dynamic changes in expression of different ischemia and regeneration-related genes of CMCs, depending from the culture condition, with stronger expression of HIF-1 α, RhoA and IL-18 if the hypoxic CMC were subjected to the secretome of MSCs.

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Cardiomyocyte-derived CXCL12 is not involved in cardiogenesis but plays a crucial role in myocardial infarction

Cited by 18 publications

References 48 publications

Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration

Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration

Platelet-derived β2m regulates age related monocyte/macrophage functions

Comparative Effect of MSC Secretome to MSC Co-culture on Cardiomyocyte Gene Expression Under Hypoxic Conditions in vitro

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