title: Pulsed focused ultrasound pretreatment improves mesenchymal stromal cell efficacy in preventing and rescuing established acute kidney injury in mice.
abstract: Animal studies have shown that mesenchymal stromal cell (MSC) infusions improve acute kidney injury (AKI) outcomes when administered early after ischemic/reperfusion injury or within 24 hours after cisplatin administration. These findings have spurred several human clinical trials to prevent AKI. However, no specific therapy effectively treats clinically obvious AKI or rescues renal function once advanced injury is established. We investigated if noninvasive image-guided pulsed focused ultrasound (pFUS) could alter the kidney microenvironment to enhance homing of subsequently infused MSC. To examine the efficacy of pFUS-enhanced cell homing in disease, we targeted pFUS to kidneys to enhance MSC homing after cisplatin-induced AKI. We found that pFUS enhanced MSC homing at 1 day post-cisplatin, prior to renal functional deficits, and that enhanced homing improved outcomes of renal function, tubular cell death, and regeneration at 5 days post-cisplatin compared to MSC alone. We then investigated whether pFUS+MSC therapy could rescue established AKI. MSC alone at 3 days post-cisplatin, after renal functional deficits were obvious, significantly improved 7-day survival of animals. Survival was further improved by pFUS and MSC. pFUS prior to MSC injections increased IL-10 production by MSC that homed to kidneys and generated an anti-inflammatory immune cell profile in treated kidneys. This study shows pFUS is a neoadjuvant approach to improve MSC homing to diseased organs. pFUS with MSC better prevents AKI than MSC alone and allows rescue therapy in established AKI, which currently has no meaningful therapeutic options.
authors: Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Imaging Sciences Training Program, Clinical Center and National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA.
authors: Scott R
authors: SR
authors: Burks
authors: Ben A
authors: BA
authors: Nguyen
authors: Pamela A
authors: PA
authors: Tebebi
authors: Saejeong J
authors: SJ
authors: Kim
authors: Michele N
authors: MN
authors: Bresler
authors: Ali
authors: A
authors: Ziadloo
authors: Jonathan M
authors: JM
authors: Street
authors: Peter S T
authors: PS
authors: Yuen
authors: Robert A
authors: RA
authors: Star
authors: Joseph A
authors: JA
authors: Frank
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology / Q000628:therapy*; D000818:Animals; D005260:Female; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D008809:Mice, Inbred C3H; D016896:Treatment Outcome; D000069453:Ultrasonic Waves
keywords: Acute kidney injury; Cellular therapy; Cisplatin; Kidney; Mesenchymal stromal cells; Renal; Renal failure; Stem cell transplantation
references: Nat Rev Nephrol. 2013 Mar;9(3):133-5
references: 23399583
references: Circ Res. 2010 Jun 11;106(11):1753-62
references: 20378860
references: Kidney Int. 1998 Dec;54(6):1817-31
references: 9853246
references: Life Sci. 1983 Feb 14;32(7):685-90
references: 6338333
references: Am J Physiol Renal Physiol. 2007 May;292(5):F1626-35
references: 17213465
references: Nephron Physiol. 2007;107(3):p65-76
references: 17940346
references: Clin J Am Soc Nephrol. 2006 Jan;1(1):43-51
references: 17699189
references: Ultrasound Med Biol. 2009 Oct;35(10):1722-36
references: 19616368
references: J Am Soc Nephrol. 2007 Sep;18(9):2486-96
references: 17656474
references: Stem Cells Dev. 2009 Jun;18(5):683-92
references: 19099374
references: Am J Kidney Dis. 2013 Feb;61(2):300-9
references: 22938846
references: Ultrasound Med Biol. 2012 Apr;38(4):661-9
references: 22390991
references: Kidney Int. 1999 Jun;55(6):2423-32
references: 10354291
references: Am J Physiol Renal Physiol. 2014 May 15;306(10):F1222-35
references: 24623144
references: Stem Cells Dev. 2013 Dec 1;22(23):3074-86
references: 23844841
references: Stem Cells. 2012 Jun;30(6):1216-27
references: 22593018
references: Am J Kidney Dis. 2000 Oct;36(4):767-74
references: 11007679
references: Stem Cell Rev. 2014 Aug;10(4):587-99
references: 24752328
references: Kidney Int. 2007 Apr;71(7):619-28
references: 17311071
references: Semin Dial. 2009 Nov-Dec;22(6):629-35
references: 20017833
references: Am J Physiol Renal Physiol. 2011 Jan;300(1):F207-18
references: 20943766
references: Stem Cells. 2008 Aug;26(8):2075-82
references: 18499895
references: Nephrology (Carlton). 2012 Jan;17(1):1-10
references: 21777348
references: J Neurosurg. 2009 Jun;110(6):1189-97
references: 19301973
references: J Am Soc Nephrol. 2013 Sep;24(9):1451-60
references: 23907510
references: Cell Transplant. 2010;19(6):667-79
references: 20525442
references: Stem Cells. 2013 Sep;31(9):1731-6
references: 23766020
references: Cell Stem Cell. 2011 Jul 8;9(1):11-5
references: 21726829
references: J Clin Invest. 2014 Jun;124(6):2355-63
references: 24892710
references: Ultrasonics. 2012 Feb;52(2):281-6
references: 21937069
references: PLoS One. 2011;6(11):e27877
references: 22114718
references: Transplant Proc. 2007 Mar;39(2):573-6
references: 17362785
references: Kidney Int Suppl (2011). 2011 Sep;1(3):90-93
references: 25028629
references: J Magn Reson Imaging. 2007 Jun;25(6):1179-91
references: 17520738
references: Brain Res. 2010 Jun 2;1334:84-92
references: 20382136
references: Trans Am Clin Climatol Assoc. 2012;123:54-62; discussion 62-3
references: 23303968
references: Am J Physiol Renal Physiol. 2014 Apr 1;306(7):F724-33
references: 24477687
references: Radiology. 2011 Apr;259(1):39-56
references: 21436096
references: J Clin Invest. 2002 Sep;110(6):835-42
references: 12235115
references: J Mol Cell Cardiol. 2006 Jun;40(6):799-809
references: 16678200
references: Clin J Am Soc Nephrol. 2012 May;7(5):851-5
references: 22442188
references: Cell Stem Cell. 2009 Mar 6;4(3):206-16
references: 19265660
references: Transplant Proc. 2013 Mar;45(2):503-10
references: 23498785
references: J Mol Cell Cardiol. 2009 Sep;47(3):411-8
references: 19540842
references: Cell Death Differ. 2014 Feb;21(2):216-25
references: 24185619
references: J Clin Invest. 2012 Nov;122(11):3931-42
references: 23093781
references: Cytotherapy. 2014 Jun;16(6):734-49
references: 24801377
references: Blood. 2011 Dec 15;118(25):e184-91
references: 22034631
references: Stem Cells. 2013 Nov;31(11):2551-60
references: 23922277
references: Hum Pathol. 2011 Aug;42(8):1132-41
references: 21315412
references: Clin Nephrol. 2008 Dec;70(6):453-63
references: 19049701
references: Stem Cells Dev. 2012 Jul 20;21(11):1911-23
references: 22066606
references: Stem Cells Int. 2012;2012:342968
references: 22754575
references: Nat Rev Nephrol. 2010 Mar;6(3):179-83
references: 20186233
references: Stem Cells. 2011 Oct;29(10):1549-58
references: 21898680
references: Stem Cells Dev. 2012 Nov 1;21(16):2969-80
references: 22563951
references: Nat Med. 2009 Jan;15(1):42-9
references: 19098906
references: PLoS One. 2011;6(9):e24730
references: 21931834
references: N Engl J Med. 1997 Mar 20;336(12):828-34
references: 9062091
references: Kidney Int. 2006 Sep;70(6):1120-6
references: 16850028
references: Immunobiology. 2013 Jan;218(1):28-39
references: 22445076
references: Cancer Res. 2013 Mar 15;73(6):1892-9
references: 23302230
references: Stem Cells Int. 2012;2012:392050
references: 23319959
references: Am J Physiol Renal Physiol. 2004 Jun;286(6):F1116-9
references: 14970000
references: Curr Drug Targets. 2009 Dec;10(12):1205-11
references: 19715536