Mechanisms of paracrine cardioprotection by cord blood mesenchymal stromal cells

Bader, Andreas Matthaeus; Brodarac, A; Klose, Kristin; Bieback, Karen; Choi, Yeong‐Hoon; Kurtz, Armin; Stamm, Christof

doi:10.1093/ejcts/ezt576

Cited by 18 publications

(21 citation statements)

References 25 publications

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“…As we and others have shown before, MSC-secreted factors are able to activate STAT3 in skeletal and cardiac myocytes as well as in cardiac progenitor cells [12,27,28,29]. However, STAT3 is not in every cell type a key mediator of the cytoprotective stem cell action [12]. In our model, STAT3 was prominently activated in HUVECs in the presence of CBMSC-conditioned medium, and when STAT3 phosphorylation was blocked, the beneficial effect was completely abolished.…”

Section: Discussionmentioning

confidence: 83%

“…As we have previously shown, both CBMSC- and FB-conditioned medium contain growth factors like vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) [12]. In addition to such soluble factors, protein- and RNA-containing microvesicles are also known to be released from cells in the culture medium [14].…”

Section: Resultsmentioning

confidence: 99%

“…The janus kinase (JAK)/STAT pathway is also known to mediate cytoprotection [25,26]. As we and others have shown before, MSC-secreted factors are able to activate STAT3 in skeletal and cardiac myocytes as well as in cardiac progenitor cells [12,27,28,29]. However, STAT3 is not in every cell type a key mediator of the cytoprotective stem cell action [12].…”

Section: Discussionmentioning

confidence: 99%

“…With a seeding density of 700 - 1000 cells/cm 2 and harvesting at subconfluency, CBMSCs were expanded to the fourth passage and cultured in Dulbecco's Modified Eagle Medium (DMEM) 21885 (low glucose), supplemented with 10% FBS, 100 U/ml penicillin, and 100 µg/ml streptomycin at 37 °C and 5% CO 2 in a humid atmosphere (all reagents from Life Technologies, Carlsbad, California, USA). The phenotype of the cultured MSCs as well as their ability to differentiate into non-hematopoietic cell types were previously confirmed [12,13]. CRL-2429™ fibroblasts from human foreskin were purchased in passage four from LGC Standards, Wesel, Germany.…”

Section: Methodsmentioning

confidence: 99%

“…Concentration of the medium by volume reduction was not performed. CBMSC/fibroblast viability after conditioned medium preparation was verified as previously described [12]. …”

Section: Methodsmentioning

confidence: 99%

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Cord Blood Mesenchymal Stromal Cell-Conditioned Medium Protects Endothelial Cells via STAT3 Signaling

Bader

Brodarac

Klose

et al. 2014

Cell Physiol Biochem

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Background/Aims: Cell-based therapies may be useful for treating ischemic diseases, but the underlying mechanisms are incompletely understood. We investigated the impact of cord blood mesenchymal stromal cell (CBMSC)- or fibroblast (FB)-secreted factors on starved endothelial cells and determined the relevant intracellular signaling pathways. Methods: HUVECs were subjected to glucose/serum deprivation (GSD) in hypoxia or normoxia, in presence of CBMSC- or FB-conditioned medium (CM). Viability and proliferation were determined via WST-8 conversion and BrdU incorporation. Apoptosis was quantified by annexin V/ethidium homodimer-III staining, nuclear fragmentation and cell morphology. mRNA expression and protein phosphorylation were determined by real-time qPCR and western blot. Experiments were repeated in presence of small-molecule inhibitors. Results: The negative impact of GSD was most pronounced at 21% O₂. Here, medium of CBMSCs and FBs increased viability and proliferation and reduced apoptosis of HUVECs. This was associated with increased STAT3 and ERK1/2 phosphorylation and BCL-2 expression. Under STAT3 inhibition, the beneficial effect of CBMSC-CM on viability and BCL-2 expression was abolished. Conclusion: Factors released by CBMSCs protect endothelial cells from the deleterious impact of GSD by activation of the STAT3 survival pathway. However, this phenomenon is not CBMSC-specific and can be reproduced using juvenile fibroblasts.

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Section: Discussionmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Concentration of the medium by volume reduction was not performed. CBMSC/fibroblast viability after conditioned medium preparation was verified as previously described [12]. …”

Section: Methodsmentioning

confidence: 99%

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Cord Blood Mesenchymal Stromal Cell-Conditioned Medium Protects Endothelial Cells via STAT3 Signaling

Bader

Brodarac

Klose

et al. 2014

Cell Physiol Biochem

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Comparison of the immunomodulatory effect of single MSC batches versus pooled MSC products

et al. 2019

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The cytoprotective capacity of processed human cardiac extracellular matrix

Kappler

Anić

Becker

et al. 2016

J Mater Sci: Mater Med

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Freshly isolated human cardiac extracellular matrix sheets (cECM) have been shown to support stem cell proliferation and tissue-specific lineage commitment. We now developed a protocol for standardized production of durable, bio-functional hcECM microparticles and corresponding hydrogel, and tested its cytoprotective effects on contractile cells subjected to ischemia-like conditions. Human ventricular myocardium was decellularized by a 3-step protocol, including Tris/EDTA, SDS and serum incubation (cECM). Following snap-freezing and lyophilization, microparticles were created and characterized by laser diffraction, dynamic image analysis (DIA), and mass spectrometry. Moreover, cECM hydrogel was produced by pepsin digestion. Baseline cell-support characteristics were determined using murine HL-1 cardiomyocytes, and the cytoprotective effects of ECM products were tested under hypoxia and glucose/serum deprivation. In cECM, glycoproteins (thrombospondin 1, fibronectin, collagens and nidogen-1) and proteoglycans (dermatopontin, lumican and mimecan) were preserved, but residual intracellular and blood-borne proteins were also detected. The median particle feret diameter was 66 μm (15-157 μm) by laser diffraction, and 57 μm (20-182 μm) by DIA with crystal violet staining. HL-1 cells displayed enhanced metabolic activity (39 ± 12 %, P < 0.05) and proliferation (16 ± 3 %, P < 0.05) when grown on cECM microparticles in normoxia. During simulated ischemia, cECM microparticles exerted distinct cytoprotective effects (MTS conversion, 240 ± 32 %; BrdU uptake, 45 ± 14 %; LDH release, -72 ± 7 %; P < 0.01, each). When cECM microparticles were solubilized to form a hydrogel, the cytoprotective effect was initially abolished. However, modifying the preparation process (pepsin digestion at pH 2 and 25 °C, 1 mg/ml final cECM concentration) restored the cytoprotective cECM activity. Extracellular matrix from human myocardium can be processed to yield standardized durable microparticles that exert specific cytoprotective effects on cardiomyocyte-like cells. The use of processed cECM may help to optimize future clinical-grade myocardial tissue engineering approaches.

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Mechanisms of paracrine cardioprotection by cord blood mesenchymal stromal cells

Cited by 18 publications

References 25 publications

Cord Blood Mesenchymal Stromal Cell-Conditioned Medium Protects Endothelial Cells via STAT3 Signaling

Cord Blood Mesenchymal Stromal Cell-Conditioned Medium Protects Endothelial Cells via STAT3 Signaling

Comparison of the immunomodulatory effect of single MSC batches versus pooled MSC products

The cytoprotective capacity of processed human cardiac extracellular matrix

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