Functionalized scaffold-mediated interleukin 10 gene delivery significantly improves survival rates of stem cells in vivo.
While stem cell transplantation could potentially treat a variety of disorders, clinical studies have not yet demonstrated conclusive benefits. This may be partly because transplanted stem cells have low survival rates, potentially due to host inflammation. The system described herein used two different gene therapy techniques to improve retention of rat mesenchymal stem cells. In the first, stem cells were transfected with interleukin-10 (IL-10) before being loaded into a collagen scaffold. In the second, unmodified stem cells were loaded into a collagen scaffold along with polymer-complexed IL-10 plasmids. The scaffolds were surgically implanted into the dorsum of syngeneic rats. At each endpoint, the scaffolds were explanted and cell retention, IL-10 level and inflammatory response were quantified. All treatment groups had statistically significant increases in cell retention after 7 days, but the group treated with 2 µg of IL-10 polyplexes had a significant improvement even at 21 days. This cell retention was associated with increased IL-10 and decreased levels of proinflammatory cytokines and apoptosis. The primary effect on the inflammatory response appeared to be on macrophage differentiation, encouraging the regulatory phenotype over the cytotoxic lineage. Improving cell survival may be an important step toward realization of the therapeutic potential of stem cells.
Network of Excellence for Functional Biomaterials, National University of Ireland, Galway, Ireland.
Carolyn
C
Holladay
Karen
K
Power
Michael
M
Sefton
Timothy
T
O'Brien
William M
WM
Gallagher
Abhay
A
Pandit
D000818:Animals; D002470:Cell Survival / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018014:Gene Transfer Techniques; D007249:Inflammation / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D054457:Tissue Scaffolds; D014185:Transplantation, Isogeneic
D016753:Interleukin-10; D003094:Collagen
Kardiol Pol. 2008 Dec;66(12):1279-85
19169974
Eur J Immunol. 1999 Mar;29(3):958-63
10092100
Am Heart J. 2007 Feb;153(2):212.e1-7
17239678
N Engl J Med. 2006 Sep 21;355(12):1210-21
16990384
Diabetes. 2009 Nov;58(11):2574-82
19690061
Ann Thorac Surg. 2009 Nov;88(5):1714-22
19853156
Transplantation. 2006 Dec 27;82(12):1733-7
17198268
J Gene Med. 2009 Sep;11(9):743-53
19554624
Adv Exp Med Biol. 2010;671:105-16
20455499
Eur Heart J. 2009 Dec;30(24):2978-84
19773226
Diabetes Metab. 2009 Sep;35(4):251-60
19539513
Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2010 May-Jun;2(3):232-48
20063367
J Control Release. 2009 Jun 19;136(3):220-5
19233237
Nature. 2001 Apr 5;410(6829):701-5
11287958
Circulation. 2000 Mar 7;101(9):1019-26
10704170
Heart Fail Rev. 2009 Jun;14(2):113-23
18712475
Curr Probl Cardiol. 2008 Mar;33(3):91-153
18243902
Circ Res. 1996 Feb;78(2):283-8
8575072
Eur Heart J. 2009 Jun;30(11):1313-21
19208649
Cell Mol Life Sci. 2009 Mar;66(5):757-72
18989624
J Heart Lung Transplant. 2002 Nov;21(11):1188-200
12431492
Blood. 2006 Sep 15;108(6):2114-20
16690970
Nat Rev Immunol. 2008 Dec;8(12):958-69
19029990
Am Heart J. 2008 Jan;155(1):55.e1-9
18082489
Nat Rev Cardiol. 2009 Sep;6(9):567-8
19696777
Eur J Pharmacol. 2008 May 13;585(2-3):261-9
18410915
Biomaterials. 2009 Mar;30(8):1482-91
19121538
Ann N Y Acad Sci. 1995 Mar 27;752:267-85
7755272
Science. 1994 Apr 1;264(5155):31
8140416
Tissue Eng. 2006 Jan;12(1):9-19
16499438
Diabetes. 2002 Apr;51(4):1088-92
11916930
Ann Thorac Surg. 1996 Feb;61(2):772-3
8572819
Vasa. 2007 Nov;36(4):241-51
18357916
Am J Physiol. 1996 Oct;271(4 Pt 1):L566-71
8897903
J Cereb Blood Flow Metab. 2000 Oct;20(10):1393-408
11043902
Heart. 2009 Dec;95(24):1983-9
19833610
Biomaterials. 2009 Feb;30(5):730-5
19038442
Circ Res. 2008 Jul 18;103(2):203-11
18566343
Annu Rev Immunol. 2001;19:683-765
11244051
Eur J Heart Fail. 2008 Aug;10(8):733-9
18599346
Eur Heart J. 2006 Dec;27(23):2775-83
17098754
Eur J Immunol. 2004 Dec;34(12):3508-15
15549732
Biomaterials. 2008 Jul;29(21):3143-51
18442851
J Clin Invest. 2010 Jan;120(1):29-40
20051634
Cancer Gene Ther. 2008 Jan;15(1):51-9
17992202
Circulation. 2005 Feb 22;111(7):913-9
15710762
J Clin Invest. 1997 Apr 1;99(7):1645-50
9120008
Hum Gene Ther. 2010 Jun;21(6):713-27
20102275
Ann N Y Acad Sci. 2006 Oct;1079:313-9
17130572
Basic Res Cardiol. 1994 Nov-Dec;89(6):499-509
7702539