Multipotent adult progenitor cells prevent macrophage-mediated axonal dieback and promote regrowth after spinal cord injury.
Macrophage-mediated axonal dieback presents an additional challenge to regenerating axons after spinal cord injury. Adult adherent stem cells are known to have immunomodulatory capabilities, but their potential to ameliorate this detrimental inflammation-related process has not been investigated. Using an in vitro model of axonal dieback as well as an adult rat dorsal column crush model of spinal cord injury, we found that multipotent adult progenitor cells (MAPCs) can affect both macrophages and dystrophic neurons simultaneously. MAPCs significantly decrease MMP-9 (matrix metalloproteinase-9) release from macrophages, effectively preventing induction of axonal dieback. MAPCs also induce a shift in macrophages from an M1, or "classically activated" proinflammatory state, to an M2, or "alternatively activated" antiinflammatory state. In addition to these effects on macrophages, MAPCs promote sensory neurite outgrowth, induce sprouting, and further enable axons to overcome the negative effects of macrophages as well as inhibitory proteoglycans in their environment by increasing their intrinsic growth capacity. Our results demonstrate that MAPCs have therapeutic benefits after spinal cord injury and provide specific evidence that adult stem cells exert positive immunomodulatory and neurotrophic influences.
Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Sarah A
SA
Busch
Jason A
JA
Hamilton
Kevin P
KP
Horn
Fernando X
FX
Cuascut
Rochelle
R
Cutrone
Nicholas
N
Lehman
Robert J
RJ
Deans
Anthony E
AE
Ting
Robert W
RW
Mays
Jerry
J
Silver
D000818:Animals; D001369:Axons / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D007150:Immunohistochemistry; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D039902:Multipotent Stem Cells / Q000502:physiology*; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000502:physiology*; D020671:Posterior Horn Cells / Q000166:cytology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000503:physiopathology
D020780:Matrix Metalloproteinase 9
J Neurosci. 2005 May 11;25(19):4694-705
15888645
Neurosurgery. 2006 Nov;59(5):957-82; discussion 982-7
17143232
J Immunol. 2000 Jun 1;164(11):5952-60
10820278
Nat Rev Immunol. 2003 Jan;3(1):23-35
12511873
J Neurotrauma. 2007 Sep;24(9):1513-28
17892412
Nat Med. 2005 May;11(5):572-7
15821747
Neuron. 1999 May;23(1):83-91
10402195
Restor Neurol Neurosci. 2009;27(4):307-21
19738324
Nat Neurosci. 2005 Mar;8(3):346-53
15711542
Neurosurg Focus. 2008;24(3-4):E19
18341395
J Cell Biochem. 2006 Aug 1;98(5):1076-84
16619257
J Cereb Blood Flow Metab. 2008 Feb;28(2):329-40
17637706
Cell Immunol. 2009;255(1-2):55-60
19022422
Bone Marrow Transplant. 2007 Oct;40(7):609-19
17603514
Stroke. 2005 Aug;36(8):1808-13
16020764
J Neurosci. 2009 Oct 28;29(43):13435-44
19864556
J Neurosci. 2009 Nov 25;29(47):14932-41
19940189
J Neurosci. 2006 Jul 12;26(28):7405-15
16837588
J Neurosci. 2002 Sep 1;22(17):7526-35
12196576
J Neurosci. 2007 Sep 5;27(36):9545-59
17804616
J Cereb Blood Flow Metab. 2010 May;30(5):1008-16
20068579
J Neurosci. 2010 Jan 6;30(1):255-65
20053907
Nat Rev Neurosci. 2005 Dec;6(12):931-44
16288297
Nat Neurosci. 2009 Sep;12(9):1106-13
19648914
J Neurosci. 1999 Oct 1;19(19):8182-98
10493720
Nature. 2002 Jul 4;418(6893):41-9
12077603
Crit Rev Oncol Hematol. 2008 Jan;65(1):81-93
18032062
Neuron. 2009 Oct 29;64(2):165-72
19874785
Expert Opin Biol Ther. 2007 Feb;7(2):173-84
17250456
J Neurosci. 2003 Mar 15;23(6):2284-93
12657687
J Neurosci. 2003 Oct 15;23(28):9276-88
14561854
Cell Stem Cell. 2008 Jul 3;3(1):16-24
18593555
J Neurotrauma. 2006 Mar-Apr;23(3-4):479-95
16629631
J Neurosci. 2008 Sep 17;28(38):9330-41
18799667
Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14638-43
18794523
Neurosurg Focus. 2008;24(3-4):E20
18341397
J Neurosci. 2004 Jul 21;24(29):6531-9
15269264
Nat Rev Neurosci. 2007 Jan;8(1):57-69
17180163
Science. 1981 Nov 20;214(4523):931-3
6171034
Exp Hematol. 2002 Aug;30(8):896-904
12160841
J Neurosci. 2009 Aug 12;29(32):9967-76
19675231
J Neurosci. 2006 Apr 5;26(14):3829-39
16597737
Blood. 2006 Jul 15;108(2):575-83
16556895
Curr Opin Neurobiol. 2006 Feb;16(1):111-8
16418002
Nat Rev Neurosci. 2004 Feb;5(2):146-56
14735117
J Cereb Blood Flow Metab. 2008 Nov;28(11):1804-10
18594556
Nat Med. 2004 Jun;10(6):610-6
15156204
Science. 2008 Nov 7;322(5903):963-6
18988856
Circ Res. 2008 Nov 21;103(11):1204-19
19028920
Exp Neurol. 2002 Mar;174(1):11-20
11869029
Glia. 1996 Jan;16(1):16-26
8787770
Cytotherapy. 2007;9(5):477-87
17786609
J Neurosci. 2010 Feb 3;30(5):1657-76
20130176
J Neurosci. 2001 May 15;21(10):3392-400
11331369
J Neurosci Res. 2009 May 15;87(7):1509-21
19115417
J Neurosci. 2009 Mar 25;29(12):3956-68
19321792