京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18131号 / 医博第3851号 / 新制||医||1001(附属図書館) / 30989 / 京都大学大学院医学研究科医学専攻 / (主査)教授 千葉 勉, 教授 坂井 義治, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19398号 / 医博第4049号 / 新制||医||1012(附属図書館) / 32423 / 京都大学大学院医学研究科医学専攻 / (主査)教授 戸口田 淳也, 教授 妻木 範行, 教授 井上 治久 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Acute myeloid leukemia (AML), a blood malignancy resulting in abnormal hematopoiesis, is associated with alterations in the bone marrow environment (BME). Current treatments for this heterogeneous disease, mainly targeting the leukemic cells, are largely unsuccessful for the majority of AML subtypes. By better understanding the mechanisms by which the BME contributes to leukemogenesis, it may be possible to introduce more effective treatments for AML. Mesenchymal stromal/stem cells (MSCs) are essential cellular components of the BME/hematopoietic niche and have been shown to support normal hematopoiesis. As a critical component, they may have several roles in altering the BME, thus providing an excellent model for studying the BME in-vitro. Several studies have characterized AML-derived MSCs (AML-MSCs). However, their exact role in altering BME remains unclear. Here, we investigated the MSCs' potential role in BME alteration by investigating the genetic profiles of previously characterized AMLMSCs (n=29) and healthy donor MSCs (HD-MSCs) (n=8). We identified that among 7565 common genes, 21 genes were significantly differentially expressed in AMLMSCs. The CD248 gene was identified among these significantly upregulated genes in AML/HD-MSCs (n=29). Focusing on AML-MSCs derived from high-risk patients (HR), CD248 protein was investigated and validated using HR AML-MSCs (n=11) and HD-MSCs (n=4). Interestingly, it was highly abundant in HR samples at the intracellular and cell-surface levels. CD248 is an MSC marker and has a biological significance potentially on their function. To better understand its potential role in MSC, CD248 was knocked down (KD) in HD-MSCs using siRNA (siCD248-MSCs). Functional capacity, the ability of HD-MSCs and siCD248-MSCs to differentiate into cell types that form the BME (adipocytes and osteocytes), and their ability to promote the growth of HL60 human leukemia cell line were assessed. Posttransfection functional assessments showed that siCD248-MSCs had a reduced adipogenic but not osteogenic potential via differentiation assays. Quantitative validation of the adipogenesis pathway by qRT-PCR confirmed the reduction. KD CD248 increased SIRT2 expression and potentially led to adipogenesis inhibition. However, co-culture experiments showed no effect of HD-MSCs or siCD248-MSCs on HL60 proliferation. Together these data showed that CD248 is a potential player in adipogenesis, essential to MSC’s functionality. Thus, it could serve as a prognostic marker and target for AML therapy.

Preterm birth (<37 weeks) is the world’s principal cause of death of children <5 years of age. Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth. BPD is characterized by an arrest in alveolar and vascular development within the lung. It is a multifactorial disease, caused by a combination of supplemental oxygen, mechanical ventilation, and inflammation. BPD is also an independent risk factor for abnormal neurodevelopment. The link between BPD and abnormal neurodevelopment is poorly understood and there are currently no effective cures for these complications. We hypothesized that a crucial cell population for brain development, i.e., the neural progenitor cell (NPC) is functionally impaired in BPD and that this impairment is associated with abnormal neurodevelopment. Based on our previous findings, we also predicted that human umbilical cord-mesenchymal stromal cell (UC-MSC) extracellular vesicles (EVs), could mitigate both the lung and brain injuries in experimental BPD. We utilized several animal models of BPD, across multiple species, to determine the effects of hyperoxia, mechanical ventilation, and inflammation on the developing lungs and brain. We also utilized UC- MSC therapy to mitigate these injuries. We discovered that hyperoxia exposure damages the developing lungs as well as the brain, leading to cerebrovascular and NPC impairments, as well as reduced neurogenesis. These impairments were associated with neurobehavioural deficits in adulthood. Furthermore, we found that inflammation in combination with mechanical ventilation and hyperoxia also impairs NPC function. Importantly, we demonstrated that UC-MSC EVs can reduce inflammation, improve vascular growth, restore lung growth, and mitigate impairments in NPC self-renewal. This work highlights novel mechanisms of BPD-associated abnormal neurodevelopment and offers potential regenerative medicine therapies to alleviate these outcomes for this vulnerable population.

京都大学 / 新制・論文博士 / 博士(医科学) / 乙第13588号 / 論医科博第11号 / 新制||医科||10(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 濵﨑 洋子, 教授 河本 宏, 教授 金子 新 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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