title: Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms.
abstract: Transplantation of whole bone marrow (BMT) as well as ex vivo-expanded mesenchymal stromal cells (MSCs) leads to striking clinical benefits in children with osteogenesis imperfecta (OI); however, the underlying mechanism of these cell therapies has not been elucidated. Here, we show that non-(plastic)-adherent bone marrow cells (NABMCs) are more potent osteoprogenitors than MSCs in mice. Translating these findings to the clinic, a T cell-depleted marrow mononuclear cell boost (> 99.99% NABMC) given to children with OI who had previously undergone BMT resulted in marked growth acceleration in a subset of patients, unambiguously indicating the therapeutic potential of bone marrow cells for these patients. Then, in a murine model of OI, we demonstrated that as the donor NABMCs differentiate to osteoblasts, they contribute normal collagen to the bone matrix. In contrast, MSCs do not substantially engraft in bone, but secrete a soluble mediator that indirectly stimulates growth, data which provide the underlying mechanism of our prior clinical trial of MSC therapy for children with OI. Collectively, our data indicate that both NABMCs and MSCs constitute effective cell therapy for OI, but exert their clinical impact by different, complementary mechanisms. The study is registered at www.clinicaltrials.gov as NCT00187018.
authors: Division of Oncology/Blood and Marrow Transplantation, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors: Satoru
authors: S
authors: Otsuru
authors: Patricia L
authors: PL
authors: Gordon
authors: Kengo
authors: K
authors: Shimono
authors: Reena
authors: R
authors: Jethva
authors: Roberta
authors: R
authors: Marino
authors: Charlotte L
authors: CL
authors: Phillips
authors: Ted J
authors: TJ
authors: Hofmann
authors: Elena
authors: E
authors: Veronesi
authors: Massimo
authors: M
authors: Dominici
authors: Masahiro
authors: M
authors: Iwamoto
authors: Edwin M
authors: EM
authors: Horwitz
mesh_terms: D000818:Animals; D001827:Body Height / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D016026:Bone Marrow Transplantation / Q000379:methods*; D001857:Bone Matrix / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D008159:Lumbar Vertebrae / Q000254:growth & development; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis; D010013:Osteogenesis Imperfecta / Q000235:genetics / Q000503:physiopathology / Q000601:surgery*; D013997:Time Factors
chemical_list: D003094:Collagen