Uckan D, Kilic E, Sharafi P, Kazik M, Kaya Fa, Erdemli E, Can A, Tezcaner A, Kocaefe C
Department of Pediatrics, Division of Hematology-Bone Marrow Transplantation Unit, University of Hacettepe Medical School, Ankara, Turkey.
Cytotherapy. 2009;11(4):392-402. doi: 10.1080/14653240802582083.
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.
BM MSC, obtained from six patients with MIOP, were expanded in vitro and characterized by morphology, plastic-adherence, immunophenotype and multilineage differentiation potential.
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-gamma, 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.
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.
恶性婴儿骨硬化症（MIOP）是一种破骨细胞疾病，其特征为骨吸收缺陷并在婴儿期死亡。多能间充质基质细胞（MSC）及其后代（成骨细胞）是骨髓（BM）微环境的主要组成部分，并且发现它们与包括破骨细胞在内的造血来源细胞紧密接触。我们推测MSC缺陷可能与破骨细胞功能障碍和骨硬化症表型相关。
从6例MIOP患者获取BM MSC，在体外进行扩增，并通过形态学、贴壁生长特性、免疫表型和多向分化潜能进行鉴定。
患者MSC的物理和免疫表型特征与年龄匹配的健康对照相似。然而，患者MSC表现出对脂肪生成谱系的体外分化缺陷，并且在诱导脂肪生成后通过脂肪生成转录本（过氧化物酶体增殖物激活受体γ、脂联素、硬脂酰辅酶A去饱和酶、瘦素和脂联素）的低表达或不表达得以证实。BM移植后，通过油红O染色显示MSC的脂肪生成能力仅有轻微改善。
MIOP在体外与MSC向脂肪生成谱系分化失败相关，提示BM微环境存在缺陷。该缺陷可能导致破骨细胞功能障碍，或者可能归因于骨硬化性骨髓环境的影响。进一步的研究应确定这一新缺陷的病理生理重要性，并且可能有助于考虑将MSC治疗用于MIOP。
