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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 prevents apoptosis in the outer medulla. (a) TUNEL staining was performed on sections of formalin fixed and paraffin-embedded kidneys from rats administered a lethal dose of cisplatin (7.5 mg/kg) and sacrificed at 5 days following cisplatin administration. The arrows indicate TUNEL positive cells. The rats were treated at 3, 9, 24, 48 and 72 hours following cisplatin administration, with 1 mL of either physiological saline (n = 4), or BMSC conditioned medium (n = 3) i.v. (b) Quantification of the TUNEL positive cells per field of view. Scale bar = 200 μm. *P < 0.01 by Student's T-test.
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fig4: BMSC-CM prevents apoptosis in the outer medulla. (a) TUNEL staining was performed on sections of formalin fixed and paraffin-embedded kidneys from rats administered a lethal dose of cisplatin (7.5 mg/kg) and sacrificed at 5 days following cisplatin administration. The arrows indicate TUNEL positive cells. The rats were treated at 3, 9, 24, 48 and 72 hours following cisplatin administration, with 1 mL of either physiological saline (n = 4), or BMSC conditioned medium (n = 3) i.v. (b) Quantification of the TUNEL positive cells per field of view. Scale bar = 200 μm. *P < 0.01 by Student's T-test.

Mentions: We next sought to analyze apoptosis in the kidneys during cisplatin toxicity. TUNEL analysis on day-5 kidney sections revealed extensive apoptotic foci in the medulla of the vehicle-treated kidneys, consistent with injury patterns in the pars recta of the proximal tubule that are precipitated by cisplatin [33] (n = 4, Figure 4(a)). We did not observe significant TUNEL positive staining in the cortex of these animals. The observed medullary apoptosis in the vehicle-treated animals was not present in the BMSC-CM treated animals (n = 3). Periodic apoptotic cells were observed in the BMSC-CM treated kidneys, but there were approximately 10X more in the vehicle-treated kidneys, indicating far fewer apoptotic events in BMSC-CM-treated kidneys (Figure 4(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 prevents apoptosis in the outer medulla. (a) TUNEL staining was performed on sections of formalin fixed and paraffin-embedded kidneys from rats administered a lethal dose of cisplatin (7.5 mg/kg) and sacrificed at 5 days following cisplatin administration. The arrows indicate TUNEL positive cells. The rats were treated at 3, 9, 24, 48 and 72 hours following cisplatin administration, with 1 mL of either physiological saline (n = 4), or BMSC conditioned medium (n = 3) i.v. (b) Quantification of the TUNEL positive cells per field of view. Scale bar = 200 μm. *P < 0.01 by Student's T-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: BMSC-CM prevents apoptosis in the outer medulla. (a) TUNEL staining was performed on sections of formalin fixed and paraffin-embedded kidneys from rats administered a lethal dose of cisplatin (7.5 mg/kg) and sacrificed at 5 days following cisplatin administration. The arrows indicate TUNEL positive cells. The rats were treated at 3, 9, 24, 48 and 72 hours following cisplatin administration, with 1 mL of either physiological saline (n = 4), or BMSC conditioned medium (n = 3) i.v. (b) Quantification of the TUNEL positive cells per field of view. Scale bar = 200 μm. *P < 0.01 by Student's T-test.
Mentions: We next sought to analyze apoptosis in the kidneys during cisplatin toxicity. TUNEL analysis on day-5 kidney sections revealed extensive apoptotic foci in the medulla of the vehicle-treated kidneys, consistent with injury patterns in the pars recta of the proximal tubule that are precipitated by cisplatin [33] (n = 4, Figure 4(a)). We did not observe significant TUNEL positive staining in the cortex of these animals. The observed medullary apoptosis in the vehicle-treated animals was not present in the BMSC-CM treated animals (n = 3). Periodic apoptotic cells were observed in the BMSC-CM treated kidneys, but there were approximately 10X more in the vehicle-treated kidneys, indicating far fewer apoptotic events in BMSC-CM-treated kidneys (Figure 4(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