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Exosomal miR-223 Contributes to Mesenchymal Stem Cell-Elicited Cardioprotection in Polymicrobial Sepsis.

Wang X, Gu H, Qin D, Yang L, Huang W, Essandoh K, Wang Y, Caldwell CC, Peng T, Zingarelli B, Fan GC - Sci Rep (2015)

Bottom Line: However, WT-MSCs were able to provide protection which was associated with exosome release.Conversely, WT-MSC-derived-exosomes displayed protective effects.By contrast, WT-exosomes encased higher levels of miR-223, which could be delivered to cardiomyocytes, resulting in down-regulation of Sema3A and Stat3.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

ABSTRACT
Mesenchymal stem cells (MSCs) have been shown to elicit cardio-protective effects in sepsis. However, the underlying mechanism remains obscure. While recent studies have indicated that miR-223 is highly enriched in MSC-derived exosomes, whether exosomal miR-223 contributes to MSC-mediated cardio-protection in sepsis is unknown. In this study, loss-of-function approach was utilized, and sepsis was induced by cecal ligation and puncture (CLP). We observed that injection of miR-223-KO MSCs at 1 h post-CLP did not confer protection against CLP-triggered cardiac dysfunction, apoptosis and inflammatory response. However, WT-MSCs were able to provide protection which was associated with exosome release. Next, treatment of CLP mice with exosomes released from miR-223-KO MSCs significantly exaggerated sepsis-induced injury. Conversely, WT-MSC-derived-exosomes displayed protective effects. Mechanistically, we identified that miR-223-KO exosomes contained higher levels of Sema3A and Stat3, two known targets of miR-223 (5p &3p), than WT-exosomes. Accordingly, these exosomal proteins were transferred to cardiomyocytes, leading to increased inflammation and cell death. By contrast, WT-exosomes encased higher levels of miR-223, which could be delivered to cardiomyocytes, resulting in down-regulation of Sema3A and Stat3. These data for the first time indicate that exosomal miR-223 plays an essential role for MSC-induced cardio-protection in sepsis.

No MeSH data available.


Related in: MedlinePlus

Loss of miR-223 in MSCs negates MSC-induced inhibitory effects on CLP-triggered systemic inflammatory response.Injection of WT-MSCs into mice at 1h post-CLP significantly reduced the circulating levels of inflammatory cytokines: (A) TNF-α, (B) IL-1β, and (C) IL-6, whereas they were not reduced in KO-MSC-treated mice, compared with PBS-treated samples. *p < 0.05, n = 4 for shams, n = 6–8 for CLP mice.
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f2: Loss of miR-223 in MSCs negates MSC-induced inhibitory effects on CLP-triggered systemic inflammatory response.Injection of WT-MSCs into mice at 1h post-CLP significantly reduced the circulating levels of inflammatory cytokines: (A) TNF-α, (B) IL-1β, and (C) IL-6, whereas they were not reduced in KO-MSC-treated mice, compared with PBS-treated samples. *p < 0.05, n = 4 for shams, n = 6–8 for CLP mice.

Mentions: It is well accepted that sepsis-triggered cardiac injury (i.e., apoptosis and dysfunction) may be indirectly linked to the presence of cardio-suppressive cytokines in serum12. Given that MSCs can exert a strong inhibitory effect on sepsis-induced systemic inflammation34567, we next measured the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in the sera collected from MSC-treated mice at 12 h post-CLP. As shown in Fig. 2A–C, under sham conditions, injection of either WT-MSCs or KO-MSCs into mice did not change the circulating levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6), compared with PBS controls. However, treatment of CLP-mice with WT-MSCs significantly reduced serum levels of TNF-α, IL-1β, and IL-6, compared to PBS-treated samples (Fig. 2A–C), which is consistent with previous reports345. By contrast, these cytokine levels only slightly decreased, but not significant, in the blood of miR-223-KO/MSC-treated CLP-mice, comparable to PBS-samples (Fig. 2A–C). Put together, these data suggest that the immune-inhibitory property of MSCs is associated with miR-223.


Exosomal miR-223 Contributes to Mesenchymal Stem Cell-Elicited Cardioprotection in Polymicrobial Sepsis.

Wang X, Gu H, Qin D, Yang L, Huang W, Essandoh K, Wang Y, Caldwell CC, Peng T, Zingarelli B, Fan GC - Sci Rep (2015)

Loss of miR-223 in MSCs negates MSC-induced inhibitory effects on CLP-triggered systemic inflammatory response.Injection of WT-MSCs into mice at 1h post-CLP significantly reduced the circulating levels of inflammatory cytokines: (A) TNF-α, (B) IL-1β, and (C) IL-6, whereas they were not reduced in KO-MSC-treated mice, compared with PBS-treated samples. *p < 0.05, n = 4 for shams, n = 6–8 for CLP mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562230&req=5

f2: Loss of miR-223 in MSCs negates MSC-induced inhibitory effects on CLP-triggered systemic inflammatory response.Injection of WT-MSCs into mice at 1h post-CLP significantly reduced the circulating levels of inflammatory cytokines: (A) TNF-α, (B) IL-1β, and (C) IL-6, whereas they were not reduced in KO-MSC-treated mice, compared with PBS-treated samples. *p < 0.05, n = 4 for shams, n = 6–8 for CLP mice.
Mentions: It is well accepted that sepsis-triggered cardiac injury (i.e., apoptosis and dysfunction) may be indirectly linked to the presence of cardio-suppressive cytokines in serum12. Given that MSCs can exert a strong inhibitory effect on sepsis-induced systemic inflammation34567, we next measured the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in the sera collected from MSC-treated mice at 12 h post-CLP. As shown in Fig. 2A–C, under sham conditions, injection of either WT-MSCs or KO-MSCs into mice did not change the circulating levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6), compared with PBS controls. However, treatment of CLP-mice with WT-MSCs significantly reduced serum levels of TNF-α, IL-1β, and IL-6, compared to PBS-treated samples (Fig. 2A–C), which is consistent with previous reports345. By contrast, these cytokine levels only slightly decreased, but not significant, in the blood of miR-223-KO/MSC-treated CLP-mice, comparable to PBS-samples (Fig. 2A–C). Put together, these data suggest that the immune-inhibitory property of MSCs is associated with miR-223.

Bottom Line: However, WT-MSCs were able to provide protection which was associated with exosome release.Conversely, WT-MSC-derived-exosomes displayed protective effects.By contrast, WT-exosomes encased higher levels of miR-223, which could be delivered to cardiomyocytes, resulting in down-regulation of Sema3A and Stat3.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

ABSTRACT
Mesenchymal stem cells (MSCs) have been shown to elicit cardio-protective effects in sepsis. However, the underlying mechanism remains obscure. While recent studies have indicated that miR-223 is highly enriched in MSC-derived exosomes, whether exosomal miR-223 contributes to MSC-mediated cardio-protection in sepsis is unknown. In this study, loss-of-function approach was utilized, and sepsis was induced by cecal ligation and puncture (CLP). We observed that injection of miR-223-KO MSCs at 1 h post-CLP did not confer protection against CLP-triggered cardiac dysfunction, apoptosis and inflammatory response. However, WT-MSCs were able to provide protection which was associated with exosome release. Next, treatment of CLP mice with exosomes released from miR-223-KO MSCs significantly exaggerated sepsis-induced injury. Conversely, WT-MSC-derived-exosomes displayed protective effects. Mechanistically, we identified that miR-223-KO exosomes contained higher levels of Sema3A and Stat3, two known targets of miR-223 (5p &3p), than WT-exosomes. Accordingly, these exosomal proteins were transferred to cardiomyocytes, leading to increased inflammation and cell death. By contrast, WT-exosomes encased higher levels of miR-223, which could be delivered to cardiomyocytes, resulting in down-regulation of Sema3A and Stat3. These data for the first time indicate that exosomal miR-223 plays an essential role for MSC-induced cardio-protection in sepsis.

No MeSH data available.


Related in: MedlinePlus