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Secreted factors from bone marrow stromal cells upregulate IL-10 and reverse acute kidney injury.

Milwid JM, Ichimura T, Li M, Jiao Y, Lee J, Yarmush JS, Parekkadan B, Tilles AW, Bonventre JV, Yarmush ML - Stem Cells Int (2012)

Bottom Line: Unfortunately, standard-of-care treatments are not sufficient for modifying the course of disease.Here we show that BMSC-secreted factors are capable of providing a survival benefit to rats subjected to cisplatin-induced AKI.In all, these results demonstrate that BMSC-secreted factors are capable of providing support without cell transplantation, and the IL-10 increase seen in BMSC-CM-treated animals correlates with attenuation of severe AKI.

View Article: PubMed Central - PubMed

Affiliation: Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School, 51 Blossom Street, Boston, MA 02114, USA ; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

ABSTRACT
Acute kidney injury is a devastating syndrome that afflicts over 2,000,000 people in the US per year, with an associated mortality of greater than 70% in severe cases. Unfortunately, standard-of-care treatments are not sufficient for modifying the course of disease. Many groups have explored the use of bone marrow stromal cells (BMSCs) for the treatment of AKI because BMSCs have been shown to possess unique anti-inflammatory, cytoprotective, and regenerative properties in vitro and in vivo. It is yet unresolved whether the primary mechanisms controlling BMSC therapy in AKI depend on direct cell infusion, or whether BMSC-secreted factors alone are sufficient for mitigating the injury. Here we show that BMSC-secreted factors are capable of providing a survival benefit to rats subjected to cisplatin-induced AKI. We observed that when BMSC-conditioned medium (BMSC-CM) is administered intravenously, it prevents tubular apoptosis and necrosis and ameliorates AKI. In addition, we observed that BMSC-CM causes IL-10 upregulation in treated animals, which is important to animal survival and protection of the kidney. In all, these results demonstrate that BMSC-secreted factors are capable of providing support without cell transplantation, and the IL-10 increase seen in BMSC-CM-treated animals correlates with attenuation of severe AKI.

No MeSH data available.


Related in: MedlinePlus

BMSC-CM significantly upregulates IL-10 in AKI rats, and BMSC-CM is not an exogenous source of IL-10. (a) Rat serum IL-10 was measured via ELISA from rats administered a lethal dose of cisplatin (7.5 mg/kg) and then treated with either vehicle or BMSC-CM at 3, 9, 24, 48, and 72 hours after cisplatin administration. Blood was collected via tail snip, and the serum was analyzed on day 3. *P < 0.05 by Student's t-test. (b) IL-10 was measured via ELISA in whole BMSC-CM.
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fig6: BMSC-CM significantly upregulates IL-10 in AKI rats, and BMSC-CM is not an exogenous source of IL-10. (a) Rat serum IL-10 was measured via ELISA from rats administered a lethal dose of cisplatin (7.5 mg/kg) and then treated with either vehicle or BMSC-CM at 3, 9, 24, 48, and 72 hours after cisplatin administration. Blood was collected via tail snip, and the serum was analyzed on day 3. *P < 0.05 by Student's t-test. (b) IL-10 was measured via ELISA in whole BMSC-CM.

Mentions: Since we saw such a strong response in the rats to BMSC-CM in AKI, we explored mechanistic implications of BMSC-CM therapy, in particular how BMSC-CM might influence the immune state of the animal during AKI. Our previous work revealed that during liver failure, the inflammatory state of rats treated with BMSC-CM was reduced compared to vehicle controls [24]: the vehicle-treated rats developed high systemic levels of IL-1β, TNF-α, IL-6, and IL-1ra, and low levels of IL-10, while BMSC-CM treated rats developed high levels of IL-10 and lower levels of IL-1β, TNF-α, IL-6 and IL-1ra. In other models as well, IL-10 upregulation has been shown to be a hallmark of BMSC therapy [13, 35], and has been shown to influence the expression of IL-1β, TNF-α, and IL-6 in vitro and in vivo [16, 36]. We evaluated whether BMSC-CM treatment resulted in enhanced IL-10 expression. The serum level of IL-10 in BMSC-CM treated rats (n = 3) three days after cisplatin administration was significantly higher than that in vehicle controls (n = 4, Figure 6(a)). To confirm that the IL-10 we measured did not arise from the BMSC-CM that we injected, we determined the amount of IL-10 in BMSC-CM. Even though the BMSC-CM was from human cells and the IL-10 we measured in the animals was rat, we nevertheless wanted to confirm there was no cross-reactivity in the ELISA and measured the BMSC-CM independently. We found that the minute positive reactivity of BMSC-CM in the ELISA could not account for the IL-10 seen in the serum (Figure 6(b)).


Secreted factors from bone marrow stromal cells upregulate IL-10 and reverse acute kidney injury.

Milwid JM, Ichimura T, Li M, Jiao Y, Lee J, Yarmush JS, Parekkadan B, Tilles AW, Bonventre JV, Yarmush ML - Stem Cells Int (2012)

BMSC-CM significantly upregulates IL-10 in AKI rats, and BMSC-CM is not an exogenous source of IL-10. (a) Rat serum IL-10 was measured via ELISA from rats administered a lethal dose of cisplatin (7.5 mg/kg) and then treated with either vehicle or BMSC-CM at 3, 9, 24, 48, and 72 hours after cisplatin administration. Blood was collected via tail snip, and the serum was analyzed on day 3. *P < 0.05 by Student's t-test. (b) IL-10 was measured via ELISA in whole BMSC-CM.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3539665&req=5

fig6: BMSC-CM significantly upregulates IL-10 in AKI rats, and BMSC-CM is not an exogenous source of IL-10. (a) Rat serum IL-10 was measured via ELISA from rats administered a lethal dose of cisplatin (7.5 mg/kg) and then treated with either vehicle or BMSC-CM at 3, 9, 24, 48, and 72 hours after cisplatin administration. Blood was collected via tail snip, and the serum was analyzed on day 3. *P < 0.05 by Student's t-test. (b) IL-10 was measured via ELISA in whole BMSC-CM.
Mentions: Since we saw such a strong response in the rats to BMSC-CM in AKI, we explored mechanistic implications of BMSC-CM therapy, in particular how BMSC-CM might influence the immune state of the animal during AKI. Our previous work revealed that during liver failure, the inflammatory state of rats treated with BMSC-CM was reduced compared to vehicle controls [24]: the vehicle-treated rats developed high systemic levels of IL-1β, TNF-α, IL-6, and IL-1ra, and low levels of IL-10, while BMSC-CM treated rats developed high levels of IL-10 and lower levels of IL-1β, TNF-α, IL-6 and IL-1ra. In other models as well, IL-10 upregulation has been shown to be a hallmark of BMSC therapy [13, 35], and has been shown to influence the expression of IL-1β, TNF-α, and IL-6 in vitro and in vivo [16, 36]. We evaluated whether BMSC-CM treatment resulted in enhanced IL-10 expression. The serum level of IL-10 in BMSC-CM treated rats (n = 3) three days after cisplatin administration was significantly higher than that in vehicle controls (n = 4, Figure 6(a)). To confirm that the IL-10 we measured did not arise from the BMSC-CM that we injected, we determined the amount of IL-10 in BMSC-CM. Even though the BMSC-CM was from human cells and the IL-10 we measured in the animals was rat, we nevertheless wanted to confirm there was no cross-reactivity in the ELISA and measured the BMSC-CM independently. We found that the minute positive reactivity of BMSC-CM in the ELISA could not account for the IL-10 seen in the serum (Figure 6(b)).

Bottom Line: Unfortunately, standard-of-care treatments are not sufficient for modifying the course of disease.Here we show that BMSC-secreted factors are capable of providing a survival benefit to rats subjected to cisplatin-induced AKI.In all, these results demonstrate that BMSC-secreted factors are capable of providing support without cell transplantation, and the IL-10 increase seen in BMSC-CM-treated animals correlates with attenuation of severe AKI.

View Article: PubMed Central - PubMed

Affiliation: Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School, 51 Blossom Street, Boston, MA 02114, USA ; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

ABSTRACT
Acute kidney injury is a devastating syndrome that afflicts over 2,000,000 people in the US per year, with an associated mortality of greater than 70% in severe cases. Unfortunately, standard-of-care treatments are not sufficient for modifying the course of disease. Many groups have explored the use of bone marrow stromal cells (BMSCs) for the treatment of AKI because BMSCs have been shown to possess unique anti-inflammatory, cytoprotective, and regenerative properties in vitro and in vivo. It is yet unresolved whether the primary mechanisms controlling BMSC therapy in AKI depend on direct cell infusion, or whether BMSC-secreted factors alone are sufficient for mitigating the injury. Here we show that BMSC-secreted factors are capable of providing a survival benefit to rats subjected to cisplatin-induced AKI. We observed that when BMSC-conditioned medium (BMSC-CM) is administered intravenously, it prevents tubular apoptosis and necrosis and ameliorates AKI. In addition, we observed that BMSC-CM causes IL-10 upregulation in treated animals, which is important to animal survival and protection of the kidney. In all, these results demonstrate that BMSC-secreted factors are capable of providing support without cell transplantation, and the IL-10 increase seen in BMSC-CM-treated animals correlates with attenuation of severe AKI.

No MeSH data available.


Related in: MedlinePlus