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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 confers a significant survival benefit to rats undergoing lethal cisplatin-induced AKI. At hour 0, cisplatin dissolved in physiological saline (0.75 mg/mL) was administered i.p. to male, SAS-SD rats at a lethal dose (7.5 mg/kg). At hours 3, 9, 24, 48, and 72, 1 mL of either physiological saline (n = 12), fibroblast conditioned medium (n = 10) or BMSC-conditioned medium (n = 14) were administered i.v. to the cisplatin-treated AKI rats. They were monitored for survival for 30 days. *P < 0.05 for BMSC-CM compared to both FB-CM and saline by Logrank test.
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fig1: BMSC-CM confers a significant survival benefit to rats undergoing lethal cisplatin-induced AKI. At hour 0, cisplatin dissolved in physiological saline (0.75 mg/mL) was administered i.p. to male, SAS-SD rats at a lethal dose (7.5 mg/kg). At hours 3, 9, 24, 48, and 72, 1 mL of either physiological saline (n = 12), fibroblast conditioned medium (n = 10) or BMSC-conditioned medium (n = 14) were administered i.v. to the cisplatin-treated AKI rats. They were monitored for survival for 30 days. *P < 0.05 for BMSC-CM compared to both FB-CM and saline by Logrank test.

Mentions: We began our studies by optimizing the cisplatin dose required to induce 75% mortality by two weeks and arrived upon 7.5 mg/kg i.p. [31]. We then determined an effective regimen for treating AKI with BMSC-CM. Previous studies illustrating the kinetics of disease onset demonstrated irreversible damage within the first 72 hours after cisplatin administration [32]. Hence, we chose five time points for repeated i.v. administration of BMSC-CM: 3, 9, 24, 48, and 72 hours after cisplatin was given. This regimen provided a significant survival benefit (Figure 1); compared to controls (FB-CM, n = 10; saline, n = 12), BMSC-CM (n = 14) improved survival from 25% to 71.4% (P < 0.05) [22]. In addition to providing a survival benefit, BMSC-CM also significantly attenuated the severity of cisplatin AKI. When animals were administered the same dose of cisplatin, BUN and creatinine rose dramatically in vehicle-treated rats by day 3 (n = 4), and continued to climb by day five, indicative of the severity of disease and irreversibility of the injury (Figures 2(a) and 2(b)). However, when the animals were treated with BMSC-CM as described above (n = 3), neither BUN nor creatinine rose dramatically at any point during the first five days after cisplatin administration. This indicated that BMSC-CM prevented extensive injury of the kidneys and preserved enough of the architecture and function of the kidneys such that clearance of BUN and creatinine was not greatly affected.


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 confers a significant survival benefit to rats undergoing lethal cisplatin-induced AKI. At hour 0, cisplatin dissolved in physiological saline (0.75 mg/mL) was administered i.p. to male, SAS-SD rats at a lethal dose (7.5 mg/kg). At hours 3, 9, 24, 48, and 72, 1 mL of either physiological saline (n = 12), fibroblast conditioned medium (n = 10) or BMSC-conditioned medium (n = 14) were administered i.v. to the cisplatin-treated AKI rats. They were monitored for survival for 30 days. *P < 0.05 for BMSC-CM compared to both FB-CM and saline by Logrank test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: BMSC-CM confers a significant survival benefit to rats undergoing lethal cisplatin-induced AKI. At hour 0, cisplatin dissolved in physiological saline (0.75 mg/mL) was administered i.p. to male, SAS-SD rats at a lethal dose (7.5 mg/kg). At hours 3, 9, 24, 48, and 72, 1 mL of either physiological saline (n = 12), fibroblast conditioned medium (n = 10) or BMSC-conditioned medium (n = 14) were administered i.v. to the cisplatin-treated AKI rats. They were monitored for survival for 30 days. *P < 0.05 for BMSC-CM compared to both FB-CM and saline by Logrank test.
Mentions: We began our studies by optimizing the cisplatin dose required to induce 75% mortality by two weeks and arrived upon 7.5 mg/kg i.p. [31]. We then determined an effective regimen for treating AKI with BMSC-CM. Previous studies illustrating the kinetics of disease onset demonstrated irreversible damage within the first 72 hours after cisplatin administration [32]. Hence, we chose five time points for repeated i.v. administration of BMSC-CM: 3, 9, 24, 48, and 72 hours after cisplatin was given. This regimen provided a significant survival benefit (Figure 1); compared to controls (FB-CM, n = 10; saline, n = 12), BMSC-CM (n = 14) improved survival from 25% to 71.4% (P < 0.05) [22]. In addition to providing a survival benefit, BMSC-CM also significantly attenuated the severity of cisplatin AKI. When animals were administered the same dose of cisplatin, BUN and creatinine rose dramatically in vehicle-treated rats by day 3 (n = 4), and continued to climb by day five, indicative of the severity of disease and irreversibility of the injury (Figures 2(a) and 2(b)). However, when the animals were treated with BMSC-CM as described above (n = 3), neither BUN nor creatinine rose dramatically at any point during the first five days after cisplatin administration. This indicated that BMSC-CM prevented extensive injury of the kidneys and preserved enough of the architecture and function of the kidneys such that clearance of BUN and creatinine was not greatly affected.

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