Three-dimensional multipotent progenitor cell aggregates for expansion, osteogenic differentiation and “in vivo” tracing with AAV vector serotype 6 View Full Text


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Article Info

DATE

2012-03-08

AUTHORS

Joäo R. Ferreira, Matthew L. Hirsch, Li Zhang, Yonsil Park, R. Jude Samulski, Wei-Shou Hu, Ching-Chang Ko

ABSTRACT

Multipotent adult progenitor cells (MAPCs) are bone marrow-derived stem cells with a high growth rate suitable for therapeutical applications as three-dimensional (3D) aggregates. Combined applications of osteogenically differentiated MAPC (OD-MAPC) aggregates and adeno-associated viral vectors (AAV) in bone bioengineering are still deferred until information with regard to expansion technologies, osteogenic potential, and AAV cytotoxicity and transduction efficiency is better understood. In this study, we tested whether self-complementary AAV (scAAV) can potentially be used as a gene delivery system in an OD-MAPC-based 'in vivo' bone formation model in the craniofacial region. Both expansion of rat MAPC (rMAPC) and osteogenic differentiation with dexamethasone were also tested in 3D aggregate culture systems 'in vitro' and 'vivo'. rMAPCs grew as undifferentiated aggregates for 4 days, with a population doubling time of 37 h. After expansion, constant levels of Oct4 transcripts, and Oct4 and CD31 surface markers were observed, which constitute a hallmark of undifferentiated stage of rMAPCs. Dexamethasone effectively mediated rMAPC osteogenic differentiation by inducing the formation of a mineralized collagen type I network, and facilitated the activation of the wnt/β-catenin, a crucial pathway in skeletal development. To investigate the genetic modification of rMAPCs grown as 3D aggregates before implantation, scAAV serotypes 2, 3 and 6 were evaluated. scAAV6 packaged with the enhanced green fluorescent protein expression cassette efficiently mediated long-term transduction (10 days) 'in vitro' and 'vivo'. The reporter transduction event allowed the tracing of OD-rMAPC (induced by dexamethasone) aggregates following OD-rMAPC transfer into a macro-porous hydroxyapatite scaffold implanted in a rat calvaria model. Furthermore, the scAAV6-transduced OD-rMAPCs generated a bone-like matrix with a collagenous matrix rich in bone-specific proteins (osteocalcin and osteopontin) in the scaffold macro-pores 10 days post-implantation. Newly formed bone was also observed in the interface between native bone and scaffold. The collective work supports future bone tissue engineering applications of 3D MAPC cultures for expansion, bone formation and the ability to alter genetically these cells using scAAV vectors. More... »

PAGES

158-168

References to SciGraph publications

  • 2007-03-12. Gene expression profiling of human mesenchymal stem cells derived from bone marrow during expansion and osteoblast differentiation in BMC GENOMICS
  • 2010-02-17. Isolation Procedure and Characterization of Multipotent Adult Progenitor Cells from Rat Bone Marrow in CELLULAR PROGRAMMING AND REPROGRAMMING
  • 2003-05-06. Von Kossa Staining Alone Is Not Sufficient to Confirm that Mineralization In Vitro Represents Bone Formation in CALCIFIED TISSUE INTERNATIONAL
  • 2010-09-30. AAV2-mediated transfer of the human aquaporin-1 cDNA restores fluid secretion from irradiated miniature pig parotid glands in GENE THERAPY
  • 2005-09-04. Genomic alterations in cultured human embryonic stem cells in NATURE GENETICS
  • 2003-12-07. Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells in NATURE BIOTECHNOLOGY
  • 2009-06-17. Proximal events in Wnt signal transduction in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 2006-08. Production and characterization of adeno-associated viral vectors in NATURE PROTOCOLS
  • 2004-04-01. Karyotype of human ES cells during extended culture in NATURE BIOTECHNOLOGY
  • 2005-01-26. Induction of chondro-, osteo- and adipogenesis in embryonic stem cells by bone morphogenetic protein-2: Effect of cofactors on differentiating lineages in BMC DEVELOPMENTAL BIOLOGY
  • 2003-11-17. Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo in GENE THERAPY
  • 2007-08-06. Comparative transcriptome analysis of embryonic and adult stem cells with extended and limited differentiation capacity in GENOME BIOLOGY
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/gt.2012.16

    DOI

    http://dx.doi.org/10.1038/gt.2012.16

    DIMENSIONS

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    PUBMED

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    35 schema:description Multipotent adult progenitor cells (MAPCs) are bone marrow-derived stem cells with a high growth rate suitable for therapeutical applications as three-dimensional (3D) aggregates. Combined applications of osteogenically differentiated MAPC (OD-MAPC) aggregates and adeno-associated viral vectors (AAV) in bone bioengineering are still deferred until information with regard to expansion technologies, osteogenic potential, and AAV cytotoxicity and transduction efficiency is better understood. In this study, we tested whether self-complementary AAV (scAAV) can potentially be used as a gene delivery system in an OD-MAPC-based 'in vivo' bone formation model in the craniofacial region. Both expansion of rat MAPC (rMAPC) and osteogenic differentiation with dexamethasone were also tested in 3D aggregate culture systems 'in vitro' and 'vivo'. rMAPCs grew as undifferentiated aggregates for 4 days, with a population doubling time of 37 h. After expansion, constant levels of Oct4 transcripts, and Oct4 and CD31 surface markers were observed, which constitute a hallmark of undifferentiated stage of rMAPCs. Dexamethasone effectively mediated rMAPC osteogenic differentiation by inducing the formation of a mineralized collagen type I network, and facilitated the activation of the wnt/β-catenin, a crucial pathway in skeletal development. To investigate the genetic modification of rMAPCs grown as 3D aggregates before implantation, scAAV serotypes 2, 3 and 6 were evaluated. scAAV6 packaged with the enhanced green fluorescent protein expression cassette efficiently mediated long-term transduction (10 days) 'in vitro' and 'vivo'. The reporter transduction event allowed the tracing of OD-rMAPC (induced by dexamethasone) aggregates following OD-rMAPC transfer into a macro-porous hydroxyapatite scaffold implanted in a rat calvaria model. Furthermore, the scAAV6-transduced OD-rMAPCs generated a bone-like matrix with a collagenous matrix rich in bone-specific proteins (osteocalcin and osteopontin) in the scaffold macro-pores 10 days post-implantation. Newly formed bone was also observed in the interface between native bone and scaffold. The collective work supports future bone tissue engineering applications of 3D MAPC cultures for expansion, bone formation and the ability to alter genetically these cells using scAAV vectors.
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    72 calvaria model
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    74 catenin
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    82 craniofacial region
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    84 culture
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    94 enhanced green fluorescent protein (eGFP) expression cassette
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    100 formation
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