Background: Malignant infantile osteopetrosis (MIOP) is a disorder of osteoclasts characterized by defective bone resorption and death in infancy. The multipotent mesenchymal stromal cells (MSC) and their progeny (osteoblasts) are major components of the bone marrow (BM) microenvironment and are found in close contact with cells of hematopoietic origin, including osteoclasts. We hypothesized that MSC defects may be associated with osteoclast dysfunction and osteopetrosis phenotype. Methods: BM MSC, obtained from six patients with MIOP, were expanded in vitro and characterized by morphology, plastic-adherence, immunophenotype and multilineage differentiation potential. Results: Physical and immunophenotypic characteristics of patient MSC were similar to healthy age-matched controls. However, an isolated in vitro differentiation defect toward adipogenic lineage was demonstrated in patient MSC and confirmed by low or absent expression of adipogenic transcripts (peroxisome proliferator-activated receptor-γ, adipophilin, stearoyl-CoA desaturase, leptin and adiponectin) upon induction of adipogenesis. Following BM transplantation, minimal improvement in adipogenic potency of MSC was demonstrated by Oil Red O staining. Discussion: MIOP is associated in vitro with a failure of MSC to differentiate into an adipogenic lineage, suggesting a BM microenvironment defect. The defect may contribute to osteoclast dysfunction, or may be attributed to the effect of the osteopetrotic marrow environment. Further investigations should determine the pathophysiologic importance of this novel defect, and could perhaps contribute to consideration of MSC therapy in MIOP.

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Keywords Adipocyte, Differentiation, Hematopoietic stem cell, Mesenchymal stromal cell, Microenvironment, Osteoclast, Osteopetrosis, Stem cell
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Journal Cytotherapy
Uckan, D, Kiliç, E, Sharafi, P, Kazik, M, Kaya, F.A, Erdemli, E, … Kocaefe, C. (2009). Adipocyte differentiation defect in mesenchymal stromal cells of patients with malignant infantile osteopetrosis. Cytotherapy, 11(4), 392–402. doi:10.1080/14653240802582083