Intrauterine bone marrow transplantation in osteogenesis imperfecta mice yields donor osteoclasts and osteomacs but not osteoblasts

Millard, Susan M., Pettit, Allison R., Ellis, Rebecca, Chan, Jerry K. Y., Raggatt, Liza J., Khosrotehrani, Kiarash and Fisk, Nicholas M. (2015) Intrauterine bone marrow transplantation in osteogenesis imperfecta mice yields donor osteoclasts and osteomacs but not osteoblasts. Stem Cell Reports, 5 5: 682-689. doi:10.1016/j.stemcr.2015.09.017


Author Millard, Susan M.
Pettit, Allison R.
Ellis, Rebecca
Chan, Jerry K. Y.
Raggatt, Liza J.
Khosrotehrani, Kiarash
Fisk, Nicholas M.
Title Intrauterine bone marrow transplantation in osteogenesis imperfecta mice yields donor osteoclasts and osteomacs but not osteoblasts
Journal name Stem Cell Reports   Check publisher's open access policy
ISSN 2213-6711
Publication date 2015-11-10
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.stemcr.2015.09.017
Open Access Status DOI
Volume 5
Issue 5
Start page 682
End page 689
Total pages 8
Place of publication Cambridge, MA United States
Publisher Cell Press (Elsevier)
Collection year 2016
Language eng
Formatted abstract
Osteogenesis imperfecta (OI) represents a spectrum of genetic disorders characterized by skeletal fragility and low-impact fractures. Severity ranges from modest fracture risk to extreme risk with intrauterine fractures and skeletal malformations. Heterogeneity results from variability in the range of causative mutations, with the vast majority directly affecting the principle protein component of bone, collagen type I, resulting in bone matrix of insufficient quantity and/or quality (Cundy, 2012). Bisphosphonates, anti-resorptive drugs that reduce bone turnover, are commonly prescribed in severe OI; while they increase bone mass, their efficacy in reducing fractures is less clear (Dwan et al., 2014 and Palomo et al., 2015). Furthermore, their mode of action does not address the underlying cause of OI and is associated with undesirable skeletal side effects in children (Rauch et al., 2007).

Cell therapy has considerable potential in treating OI, as replacing abnormal osteoblasts, the bone-forming cells with defective bone matrix production, with normal functioning osteoblasts should improve both bone quality and quantity and mimic the naturally occurring mosaic mutation carriers who demonstrate normal skeletal health (Cabral and Marini, 2004). Thus, replacement of just 25% of osteoblasts may deliver significant benefit to OI patients. Small clinical trials and isolated case studies of cell therapy for severe OI have already been undertaken, with considerable variation in transplantation protocols and donor cell source. Growth velocity transiently improved in children with OI following both bone marrow transplantation and subsequent mesenchymal stromal/stem cell (MSC) transplantation (Horwitz et al., 1999, Horwitz et al., 2001 and Horwitz et al., 2002). Clinical experience following in utero transplantation of fetal MSC is also consistent with modest transient benefit (Götherström et al., 2014 and Le Blanc et al., 2005). Given the low-level donor chimerism reported, this cannot be conclusively attributed to donor osteopoiesis. These few case studies are also subject to confounding factors of bisphosphonate co-treatment and inherent phenotypic heterogeneity of OI. While promising, the potential of cell therapy has yet to be substantiated and is now more comprehensively addressed in preclinical studies.

Preclinical models allow assessment of cell therapy in larger sample sizes with more consistent disease presentation in the absence of confounding co-therapies. The key target for cell replacement is the osteoblast that produces the collagen type I bone matrix. As such, mesenchymal stromal/stem cells (MSCs) are an obvious cell therapy candidate, as they are believed to be the source of long-term osteoblast repopulation in vivo. However, a recent study on adolescent osteogenesis imperfecta (oim/oim) mice concluded non-adherent BM cells were superior to MSC at contributing to osteopoiesis ( Otsuru et al., 2012). Furthermore, intra-uterine transplantation of murine whole BM in the Brtl IV mouse model of OI reduced perinatal lethality and was associated with improved bone biomechanics ( Panaroni et al., 2009). However, the methods to quantitate chimerism were independent of rigorous confirmation of donor cells being osteoblasts. This is of particular concern following BM transplantation, where donor cells may contribute to hematopoietic-derived bone cells, including osteoclasts and osteal macrophages ( Chang et al., 2008). Hence, the capacity of donor cells to contribute to osteopoiesis following bone marrow transplantation remains unclear. To address this, we profiled the identity of bone-associated donor cells following intra-uterine bone marrow transplantation in the oim/oim mouse.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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