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Bone Marrow Transplantation for Treatment of the Col1a2+/G610C Osteogenesis Imperfecta Mouse Model

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Abstract

Bone marrow transplantation (BMT) of healthy donor cells has been postulated as a strategy for treating osteogenesis imperfecta (OI) and other bone fragility disorders. The effect of engraftment by tail vein injection and/or marrow ablation by 6 Gy whole body irradiation were tested in Col1a2+/G610C (OI) mice as a model of mild-moderate OI. Dual-emission X-ray absorptiometry, microCT, and 4-point bending were used to measure bone volume (BV), bone mineral density (BMD), and biomechanical strength. BV, BMD, and mechanical strength were reduced in OI mice compared to wild type (WT) controls. BMT with and without irradiation yielded no difference in BV and BMD outcomes for both OI and WT mice, at 3 weeks. Transplantation of OI cells into OI mice to test for paracrine effects of BMT also showed no difference with non-transplanted OI mice. In a parallel cell tracking study, donor marrow was taken from transgenic mice constitutively expressing tdTomato and transplanted into WT mice. Lineage tracking demonstrated that irradiation considerably enhanced engraftment of tdTomato+ cells. However, tdTomato+ cells predominantly expressed TRAP and not AP, indicating engrafted donor cells were chiefly from the hematopoietic lineages. These data show that whole marrow transplantation fails to rescue the bone phenotype of Col1a2+/G610C (OI) mice and that osteopoietic engraftment is not significantly enhanced by irradiation. These findings are highly relevant to modern approaches focused on the gene repair of patient cells ex vivo and their subsequent reintroduction into the osteopoietic compartment via the circulation.

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Funding

This work was supported by philanthropic funding from the Sticks and Stones Foundation.

Author information

Authors and Affiliations

  1. Orthopaedic Research and Biotechnology Unit, Kids Research, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia

    Lucinda R. Lee, Lauren Peacock, Tegan L. Cheng, David G. Little, Craig F. Munns & Aaron Schindeler

  2. Discipline of Child and Adolescent Health, Faculty of Health and Medicine, The University of Sydney, Sydney, NSW, Australia

    Lucinda R. Lee, Laurence C. Cantrill, Tegan L. Cheng, David G. Little, Craig F. Munns & Aaron Schindeler

  3. Gene Therapy Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children’s Hospitals Network, Westmead, NSW, Australia

    Samantha L. Ginn

  4. Microscopy Services, Kids Research at The Children’s Hospital at Westmead, Westmead, NSW, Australia

    Laurence C. Cantrill

Authors
  1. Lucinda R. Lee
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  2. Lauren Peacock
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  3. Samantha L. Ginn
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  4. Laurence C. Cantrill
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  5. Tegan L. Cheng
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  7. Craig F. Munns
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  8. Aaron Schindeler
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Contributions

LRL performed the bulk of the experimental research and analysis. LP performed animal injection and animal care. SG carried out total body irradiation. LCC advised on microscopy and captured confocal images, TLC carried out biomechanical testing. DGL, CM, and AS conceived the study and designed the experimental plan. LRL and AS drafted the manuscript, with all authors providing critical feedback.

Corresponding author

Correspondence to Aaron Schindeler.

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Conflict of interest

Aaron Schindeler has received funding support from Amgen, Novartis AG, Celgene Corp, and N8 Medical for research unrelated to this study. Craig F. Munns has received research support from Alexion, Novartis AG and is a consultant for Alexion and Novartis AG for research unrelated to this project. Tegan L. Cheng and David G. Little received philanthropic funding from Hyundai Help for Kids, which is unrelated to this work.

Human and Animal Rights and Informed Consent

Animal experiments were approved by The Children’s Hospital at Westmead/Children’s Medical Research Institute Animal Ethics Committee under protocol K315. Informed Consent was not required as no human was involved.

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Lee, L.R., Peacock, L., Ginn, S.L. et al. Bone Marrow Transplantation for Treatment of the Col1a2+/G610C Osteogenesis Imperfecta Mouse Model. Calcif Tissue Int 104, 426–436 (2019). https://doi.org/10.1007/s00223-018-0504-3

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  • DOI: https://doi.org/10.1007/s00223-018-0504-3

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