Mobilized human hematopoietic stem/progenitor cells promote kidney repair after ischemia/reperfusion injury.
BACKGROUND
Understanding the mechanisms of repair and regeneration of the kidney after injury is of great interest because there are currently no therapies that promote repair, and kidneys frequently do not repair adequately. We studied the capacity of human CD34(+) hematopoietic stem/progenitor cells (HSPCs) to promote kidney repair and regeneration using an established ischemia/reperfusion injury model in mice, with particular focus on the microvasculature.


RESULTS
Human HSPCs administered systemically 24 hours after kidney injury were selectively recruited to injured kidneys of immunodeficient mice (Jackson Labs, Bar Harbor, Me) and localized prominently in and around vasculature. This recruitment was associated with enhanced repair of the kidney microvasculature, tubule epithelial cells, enhanced functional recovery, and increased survival. HSPCs recruited to kidney expressed markers consistent with circulating endothelial progenitors and synthesized high levels of proangiogenic cytokines, which promoted proliferation of both endothelial and epithelial cells. Although purified HSPCs acquired endothelial progenitor markers once recruited to the kidney, engraftment of human endothelial cells in the mouse capillary walls was an extremely rare event, indicating that human stem cell mediated renal repair is by paracrine mechanisms rather than replacement of vasculature.


CONCLUSIONS
These studies advance human HSPCs as a promising therapeutic strategy for promoting renal repair after injury.
Li
Bing
B
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cohen
Amy
A
Hudson
Thomas E
TE
Motlagh
Delara
D
Amrani
David L
DL
Duffield
Jeremy S
JS
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002196:Capillaries / Q000473:pathology; D002465:Cell Movement; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D004847:Epithelial Cells; D005355:Fibrosis / Q000517:prevention & control; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007121:Immunocompetence; D007668:Kidney / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D007684:Kidney Tubules / Q000098:blood supply / Q000503:physiopathology; D051379:Mice / Q000276:immunology; D008833:Microcirculation; D019899:Paracrine Communication; D020127:Recovery of Function; D012038:Regeneration; D015427:Reperfusion Injury / Q000503:physiopathology*; D016019:Survival Analysis; D014945:Wound Healing
D018952:Antigens, CD34; D015415:Biomarkers; D003115:Colony-Stimulating Factors; D016179:Granulocyte Colony-Stimulating Factor
J Clin Invest. 1997 Dec 1;100(11 Suppl):S25-9
9413397
N Engl J Med. 2005 Sep 8;353(10):999-1007
16148285
J Am Soc Nephrol. 2007 Nov;18(11):2921-8
17942965
Am J Pathol. 2003 Dec;163(6):2289-301
14633603
Kidney Int. 2007 Jul;72(2):151-6
17495858
Am J Pathol. 2010 Jan;176(1):85-97
20008127
J Thromb Haemost. 2006 Mar;4(3):671-7
16460450
Circ Res. 2005 Aug 19;97(4):314-22
16020753
Am J Physiol Renal Physiol. 2001 Nov;281(5):F887-99
11592947
J Immunol. 2009 Nov 15;183(10):6733-43
19864592
Nat Med. 2004 Aug;10(8):858-64
15235597
Nephrol Dial Transplant. 2008 Jul;23(7):2126-8
18587158
J Clin Invest. 2005 Jul;115(7):1743-55
16007251
Nat Med. 2003 Jun;9(6):702-12
12778169
Mod Pathol. 2008 Jul;21(7):837-46
18487998
J Clin Invest. 2004 Aug;114(3):330-8
15286799
Blood. 2005 Oct 1;106(7):2347-55
15985545
Stem Cells. 2008 Mar;26(3):819-30
18192236
J Am Soc Nephrol. 2007 Apr;18(4):1292-8
17314324
Nat Rev Cancer. 2006 Nov;6(11):835-45
17036040
Stem Cells Dev. 2009 Apr;18(3):475-85
18564903
Bone. 2008 Sep;43(3):434-9
18547890
Stem Cells. 2006 May;24(5):1185-93
16410390
Am J Pathol. 2006 Aug;169(2):372-87
16877340
J Am Soc Nephrol. 1998 Feb;9(2):231-42
9527399
Am J Pathol. 2006 Oct;169(4):1440-57
17003498
Nature. 2005 Dec 15;438(7070):932-6
16355210
Kidney Int. 2006 Jan;69(2):323-30
16408122
Kidney Int. 2008 Aug;74(3):257-8
18626492
Blood Cells. 1994;20(2-3):411-23
7538347
J Am Soc Nephrol. 2007 Sep;18(9):2486-96
17656474
Am J Physiol Cell Physiol. 2004 Sep;287(3):C572-9
15308462
Arterioscler Thromb Vasc Biol. 2005 Feb;25(2):270-1
15681306
J Mol Med (Berl). 2004 Oct;82(10):671-7
15322703
Ann Intern Med. 2002 Jan 1;136(1):54-71
11777364
J Hepatol. 2006 Jul;45(1):13-9
16635534
N Engl J Med. 1996 May 30;334(22):1448-60
8618585
J Clin Invest. 2003 Jul;112(2):160-9
12865405
J Cell Mol Med. 2009 Jan;13(1):87-102
19067770
Trends Mol Med. 2008 Jul;14(7):277-85
18554984
Thromb Haemost. 2005 Feb;93(2):228-35
15711737
J Am Soc Nephrol. 2004 May;15(5):1307-15
15100371
Am J Pathol. 2008 Dec;173(6):1617-27
19008372
Am J Physiol Renal Physiol. 2007 May;292(5):F1626-35
17213465
Hypertension. 1999 Apr;33(4):1013-9
10205240
J Am Soc Nephrol. 2009 Jan;20(1):223-8
19020007
Stem Cells Dev. 2009 Mar;18(2):229-34
18491948
Lancet. 2005 Jan 22-28;365(9456):331-40
15664230
Circulation. 2003 Oct 28;108(17):2070-3
14568894
Am J Physiol Renal Physiol. 2009 Aug;297(2):F461-70
19458120