Johansson Maria, Jansson Lina, Ehinger Mats, Fasth Anders, Karlsson Stefan, Richter Johan
Molecular Medicine and Gene Therapy, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, University Hospital of Lund, Lund, Sweden.
Exp Hematol. 2006 Feb;34(2):242-9. doi: 10.1016/j.exphem.2005.11.010.
Infantile malignant osteopetrosis (IMO) is a rare autosomal recessive disorder affecting osteoclast function. Fifty percent of the patients have a mutation in the TCIRG1 gene coding for one subunit of an osteoclast proton pump. The only curative treatment is hematopoietic stem cell transplantation (SCT). The oc/oc mouse has a mutation in the gene homologous to TCIRG1 and its expected lifespan is only 3 to 4 weeks. Previous attempts to cure these mice with SCT have been unsuccessful. We wanted to determine if early hematopoietic SCT using enriched and MHC-matched stem cells can cure oc/oc mice from osteopetrosis.
One- and 8-day-old oc/oc and control mice were radiated with 200, 400, or 600 cGy and transplanted intraperitoneally with 1 or 5 x 10(6) normal lineage-depleted bone marrow cells. Blood, x-ray, and pathology analyses were performed on transplanted mice.
All 1-day-old mice irradiated with 400 cGy and transplanted with 5 x 10(6) cells survived long term. An engraftment level of 20% is sufficient to correct most features of the disease. X-ray and histopathology examination of transplanted animals showed normalization of bone structure. However, although a correction of bone structure occurred, the transplanted oc/oc mice were smaller in size than their littermates. In contrast to untreated animals, oc/oc mice developed teeth after transplantation, but with abnormal structure and shape making them unusable.
We have shown that this murine form of IMO is curable with neonatal SCT using enriched stem cells.
婴儿恶性骨硬化症（IMO）是一种罕见的常染色体隐性疾病，影响破骨细胞功能。50%的患者在编码破骨细胞质子泵一个亚基的TCIRG1基因中存在突变。唯一的治愈性治疗方法是造血干细胞移植（SCT）。oc/oc小鼠在与TCIRG1同源的基因中存在突变，其预期寿命仅为3至4周。此前用SCT治愈这些小鼠的尝试均未成功。我们想确定使用富集且主要组织相容性复合体（MHC）匹配的干细胞进行早期造血SCT是否能治愈oc/oc小鼠的骨硬化症。
对1日龄和8日龄的oc/oc小鼠及对照小鼠进行200、400或600厘戈瑞（cGy）的辐射，并经腹腔注射1或5×10⁶个去除谱系的正常骨髓细胞。对移植后的小鼠进行血液、X线和病理学分析。
所有接受400 cGy辐射并移植5×10⁶个细胞的1日龄小鼠均长期存活。20%的植入水平足以纠正该疾病的大多数特征。对移植动物的X线和组织病理学检查显示骨结构正常化。然而，尽管骨结构得到了纠正，但移植后的oc/oc小鼠比同窝小鼠体型小。与未治疗的动物不同，oc/oc小鼠在移植后长出了牙齿，但结构和形状异常，无法使用。
我们已经表明，使用富集干细胞的新生儿SCT可治愈这种小鼠形式的IMO。
