Stem Cell Therapy as a Treatment for Osteogenesis Imperfecta

Abstract

Purpose of Review Osteogenesis imperfecta (OI) is a chronic disease with few treatment options available. The purpose of this review is to provide an overview on treating OI with mesenchymal stem cells (MSC). Recent Findings Off-the-shelf MSC have a good safety profile and exhibit multilineage differentiation potential and a low immunogenic profile and are easy to manufacture. Their ability to migrate, engraft, and differentiate into bone cells, and also to act via paracrine effects on the recipient’s tissues, makes MSC candidates as a clinical therapy for OI. Due to their high osteogenic potency, fetal MSC offer an even higher therapeutic potential in OI compared with MSC derived from adult sources. Preclinical and initial clinical data support the use of MSC in treating OI. Summary The characteristics of MSC make them of great interest in treating OI. MSC may be safely transplanted via intravenous administration and show potential positive clinical effects.

Clinical Application of Bone Marrow Mesenchymal Stem/Stromal Cells to Repair Skeletal Tissue

“…A number of musculoskeletal conditions such as osteoporosis, osteomyelitis, osteosarcoma, diabetic fracture and congenital disorders such as osteogenesis imperfecta result in a compromise or delay in skeletal formation/repair [ 88 , 89 , 90 , 91 ]. While a majority of reports have utilized exogenous autologous or allogeneic MSC, other studies have attempted to recruit endogenous MSC through the administration of bioactive signals, including but not limited to BMP, parathyroid hormone (PTH), C-X-C Motif Chemokine Ligand 12 (CXCL12), VEGF, PDGF-Rβ, Interleukin 10 (IL-10), and Leucine Rich Repeat Containing G Protein-Coupled Receptor 5 (Lgr5) signaling pathways, mediated by the above-mentioned biomimetic delivery methods [ 17 , 92 , 93 , 94 , 95 ].…”

“…However, causative genes whose proteins normally associate with collagen also result in rare recessive forms of OI, including types V-XII and unclassified as reviewed by Marini and colleagues [ 148 ]. Depending on the severity, the pathophysiology predominantly results in reduced collagen quantity or abnormal collagen microfibril assembly, while the other causative genes influence osteoblast development, matrix mineralization and hydroxylation defects [ 91 , 148 ]. The most common clinical manifestations include abnormal skeletal development, short stature, and skeletal fragility among other non-skeletal related indications [ 93 , 149 , 150 ].…”

“…The most common clinical manifestations include abnormal skeletal development, short stature, and skeletal fragility among other non-skeletal related indications [ 93 , 149 , 150 ]. Preclinical OI mouse studies have reported that MSC transplantation may be a viable option to treat OI [ 51 , 91 , 149 , 151 , 152 ]. Furthermore, priming blood-derived human fetal MSC with CXCL12 to upregulate CXCR4 expression enriches donor cell engraftment, improves bone mechanisms and reduces bone brittleness in a mouse OI model [ 150 ].…”

Mechanisms of Bone Fragility: From Osteogenesis Imperfecta to Secondary Osteoporosis

“…Recently, preclinical studies demonstrated the potential of MSC transplantation before and after birth for severe types of OI (types II/III, severe type IV); this treatment approach is currently tested in the ongoing multicenter clinical trial boost brittle bones before birth (BOOSTB4) [ 44 ]. However, one major hurdle to such a cellular therapy is low engraftment of cells in all skeletal elements.…”

Current Overview of Osteogenesis Imperfecta

“…Postnatal transplantation with same-donor foetal liver MSCs was performed at 1.6 years of age, and following the procedure, a resumption of vertical growth was observed. Based on these clinical experiences, the first clinical trial of the transplantation of foetal liver MSCs, the Boost Brittle Bones Before Birth (BOOSTB4) trial is ongoing [ 99 , 100 ]. The BOOSTB4 trial is investigating the safety and tolerability of MSC transplantation as a therapy for severe forms of OI (OI type 3 and 4).…”