Ex vivo regional gene therapy with human adipose-derived stem cells for bone repair.
Adipose derived stem cells
Bone healing
Bone regeneration
Gene therapy
Mesenchymal stem cells
Journal
Bone
ISSN: 1873-2763
Titre abrégé: Bone
Pays: United States
ID NLM: 8504048
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
22
09
2019
revised:
20
06
2020
accepted:
29
06
2020
pubmed:
6
7
2020
medline:
22
6
2021
entrez:
6
7
2020
Statut:
ppublish
Résumé
The treatment of complex bone loss scenarios remains challenging. This study evaluates the efficacy of ex vivo regional gene therapy using transduced human adipose-derived stem cells (ASCs) overexpressing bone morphogenetic protein-2 (BMP-2) to treat critical-sized bone defects. Critical-sized femoral defects created surgically in immunocompromised rats were treated with ASCs transduced with a lentivirus encoding BMP-2 (Group 1, n = 14), or green fluorescent protein (Group 2, n = 5), nontransduced ASCs (Group 3, n = 5), or rhBMP-2 (Group 4, n = 14). At 12 weeks, femurs were evaluated for quantity and quality of bone formation with plain radiographs, micro-computed tomography, histology/histomorphometry, and biomechanical strength testing. Thirteen of 14 samples in Group 1 and all 14 samples in Group 4 showed radiographic healing, while no samples in either Groups 2 or 3 healed. Groups 1 and 4 had significantly higher radiographic scores (p < 0.001), bone volume fraction (BV/TV) (p < 0.001), and bone area fraction (BA/TA) than Groups 2 and 3 (p < 0.001). Radiographic scores, BV/TV, and BA/TA were not significantly different between Groups 1 and 4. No difference with regards to mean torque, rotation at failure, torsional stiffness, and energy to failure was seen between Groups 1 and 4. Human ASCs modified to overexpress BMP-2 resulted in abundant bone formation, with the quality of bone comparable to that of rhBMP-2. This strategy represents a promising approach in the treatment of large bone defects in the clinical setting. Large bone defects may require sustained protein production to induce an appropriate osteoinductive response. Ex vivo regional gene therapy using a lentiviral vector has the potential to be part of a comprehensive tissue engineering strategy for treating osseous defects.
Sections du résumé
BACKGROUND
The treatment of complex bone loss scenarios remains challenging. This study evaluates the efficacy of ex vivo regional gene therapy using transduced human adipose-derived stem cells (ASCs) overexpressing bone morphogenetic protein-2 (BMP-2) to treat critical-sized bone defects.
METHODS
Critical-sized femoral defects created surgically in immunocompromised rats were treated with ASCs transduced with a lentivirus encoding BMP-2 (Group 1, n = 14), or green fluorescent protein (Group 2, n = 5), nontransduced ASCs (Group 3, n = 5), or rhBMP-2 (Group 4, n = 14). At 12 weeks, femurs were evaluated for quantity and quality of bone formation with plain radiographs, micro-computed tomography, histology/histomorphometry, and biomechanical strength testing.
RESULTS
Thirteen of 14 samples in Group 1 and all 14 samples in Group 4 showed radiographic healing, while no samples in either Groups 2 or 3 healed. Groups 1 and 4 had significantly higher radiographic scores (p < 0.001), bone volume fraction (BV/TV) (p < 0.001), and bone area fraction (BA/TA) than Groups 2 and 3 (p < 0.001). Radiographic scores, BV/TV, and BA/TA were not significantly different between Groups 1 and 4. No difference with regards to mean torque, rotation at failure, torsional stiffness, and energy to failure was seen between Groups 1 and 4.
CONCLUSIONS
Human ASCs modified to overexpress BMP-2 resulted in abundant bone formation, with the quality of bone comparable to that of rhBMP-2. This strategy represents a promising approach in the treatment of large bone defects in the clinical setting.
CLINICAL RELEVANCE
Large bone defects may require sustained protein production to induce an appropriate osteoinductive response. Ex vivo regional gene therapy using a lentiviral vector has the potential to be part of a comprehensive tissue engineering strategy for treating osseous defects.
Identifiants
pubmed: 32622870
pii: S8756-3282(20)30304-5
doi: 10.1016/j.bone.2020.115524
pmc: PMC7423694
mid: NIHMS1611603
pii:
doi:
Substances chimiques
Bone Morphogenetic Protein 2
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
115524Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR057076
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Références
Orthopedics. 2012 Jun;35(6):e847-54
pubmed: 22691656
Nat Rev Rheumatol. 2015 Apr;11(4):234-42
pubmed: 25776949
J Bone Joint Surg Am. 2013 Apr 17;95(8):694-701
pubmed: 23595067
Eur Cell Mater. 2013 Jul 16;26:1-12; discussion 12-4
pubmed: 23857280
Cytotherapy. 2005;7(3):273-81
pubmed: 16081354
J Bone Joint Surg Am. 1999 Jul;81(7):905-17
pubmed: 10428121
Injury. 2015 Dec;46(12):2351-8
pubmed: 26454628
Organogenesis. 2012 Oct-Dec;8(4):114-24
pubmed: 23247591
Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14595-600
pubmed: 11734653
J Bone Joint Surg Am. 2002 May;84(5):716-20
pubmed: 12004011
Lancet. 2016 Jul 30;388(10043):476-87
pubmed: 27289174
Tissue Eng. 2005 Jan-Feb;11(1-2):120-9
pubmed: 15738667
J Orthop Trauma. 2014 Oct;28(10):599-604
pubmed: 24682163
Bone. 2008 May;42(5):921-31
pubmed: 18295562
J Am Acad Orthop Surg. 2005 Jul-Aug;13(4):230-42
pubmed: 16112980
J Vis Exp. 2013 Sep 26;(79):e50585
pubmed: 24121366
J Gene Med. 2016 Aug;18(8):199-207
pubmed: 27373764
Curr Gene Ther. 2018;18(3):154-170
pubmed: 29637858
Mater Sci Eng C Mater Biol Appl. 2017 Jan 1;70(Pt 1):856-869
pubmed: 27770964
Stem Cell Res Ther. 2017 Oct 27;8(1):238
pubmed: 29078809
Breast Cancer (Auckl). 2017 Aug 16;11:1178223417726777
pubmed: 29104428
Curr Gene Ther. 2015;15(5):481-91
pubmed: 26264707
Tissue Eng. 2007 Aug;13(8):1987-93
pubmed: 17518747
Anat Rec (Hoboken). 2008 Mar;291(3):283-92
pubmed: 18228587
Tissue Eng. 2001 Apr;7(2):211-28
pubmed: 11304456
J Orthop Trauma. 1989;3(3):192-5
pubmed: 2809818
J Bone Joint Surg Am. 2011 May 4;93(9):801-8
pubmed: 21454742
Hum Gene Ther Methods. 2018 Dec;29(6):269-277
pubmed: 30280937
J Bone Miner Metab. 2007;25(1):6-11
pubmed: 17187188
J Hand Surg Am. 2016 May;41(5):602-8
pubmed: 27013317
Eur Cell Mater. 2015 Sep 21;30:118-30; discussion 130-1
pubmed: 26388615
Spine (Phila Pa 1976). 2003 Jan 15;28(2):134-9
pubmed: 12544929
N Engl J Med. 2017 Mar 2;376(9):848-855
pubmed: 28249145
Tissue Eng Part A. 2010 Mar;16(3):1093-101
pubmed: 20035609
Hum Gene Ther. 2018 Apr;29(4):507-519
pubmed: 29212377
J Bone Joint Surg Am. 2015 Nov 18;97(22):1852-9
pubmed: 26582615
Curr Gene Ther. 2013 Dec;13(6):453-68
pubmed: 24195603
Curr Pharm Des. 2013;19(19):3466-73
pubmed: 23432674
Lancet. 2017 Jul 1;390(10089):50-61
pubmed: 28526489
Injury. 2015 Nov;46(11):2267-72
pubmed: 26374949
Mol Ther. 2011 May;19(5):960-8
pubmed: 21343916
J Orthop Res. 2006 Aug;24(8):1709-21
pubmed: 16788987
J Neurosurg Pediatr. 2015 Jul;16(1):4-13
pubmed: 25860984
Bone. 2007 Apr;40(4):931-8
pubmed: 17236835
Biotech Histochem. 2012 May;87(4):303-11
pubmed: 22250760
J Bone Joint Surg Am. 2008 Feb;90 Suppl 1:99-110
pubmed: 18292364
ANZ J Surg. 2009 Apr;79(4):235-44
pubmed: 19432707
Curr Protoc Stem Cell Biol. 2017 May 16;41:1F.18.1-1F.18.23
pubmed: 28510332
J Allergy Clin Immunol. 2015 Sep;136(3):692-702.e2
pubmed: 25792466
Eur Cell Mater. 2009 Dec 31;18:96-111
pubmed: 20073015
Gene Ther. 2018 Jul;25(4):260-268
pubmed: 29907876
N Engl J Med. 2013 Apr 18;368(16):1509-1518
pubmed: 23527958
Hum Gene Ther. 2003 Jan 1;14(1):59-66
pubmed: 12573059