Download Bone marrow mesenchymal stem cell biology and the role of

A. Bone marrow mesenchymal stem cell biology and the role of chemokine Cxcl12
Regulation of the stem cell homeostasis is currently the hot topics in the stem cell biology. Unraveling the interaction between the stem cell and
its niche will provide the clues how the stem cell responds to the environment under the physiological and the pathological conditions. In the
bone marrow, the hematopoietic stem cell receives multiple signals from the surrounding cells and the mesenchymal stem cells and the
osteo-lineage cells contribute an important part. Our previous studies focused on the chemokine Cxcl12/Sdf-1 and studied its role in the postnatal
homeostasis of the hematopoietic stem cells (Refs). Using our Cxcl12 conditional knockout mice model, we successfully created the postnatal
Cxcl12 deletion model and we found that Cxcl12 is a critical niche factor while loss of Cxcl12 caused the disruption of hematopoietic stem cell
homeostasis and niche structure. Following this we mated the Cxcl12 floxed allele to several tissue-specific Cre lines to analyze the phenotypes
and found that loss of Cxcl12 in osteoprogenitors (to be specific, Osterix-expressing cells) has very similar hematopoietic stem cell phenotypes
compared to our previous whole-body knockout model. Meanwhile we tested Cxcl12 ablation in other types of cells (by mating with Tie2-Cre,
Collagen1a1-Cre, Vav1-Cre and Prx-Cre) to examine the impact to the hematopoietic system. Besides the analyses of the hematopoietic
phenotypes, we put emphasis on the less-known topic - the role of the Cxcl12 to the mesenchymal stem cell self-renewal and differentiation. We
hypothesize that Cxcl12 is not only the critical niche factor for the hematopoietic stem cells but also a crucial factor for the mesenchymal stem cell
regulation. Cxcl12 might regulate the balanced output of the osteogenic and adipogenic cells. The results are published in several annunal
research conferences and will be published in the paper format soon.
This project is one of the executing 2014 MOST project: 化學驅動激素 Cxcl12/Sdf-1 對於骨髓間葉幹細胞分化調控及在 Cxcl12 小鼠基因剔
除模式下對於骨髓血液幹細胞微環境的影響.
B. The role of the chemokine Cxcl12 signaling in the gliomagenesis and immune regulation.
Glioma is a unique tumor type that is sometimes highly proliferating accompanied with strong vascularization. In tumor biology, the chemokine
CXCL12 has been reported to involve in the tumor survival, apoptosis and metastasis. Massive data coming from different types of tumor and
study methods constituted a very bizzare and controversial picture of CXCL12 signaling system. In general, CXCL12 might regulate tumor invasion
and intratumor angiogenesis. To explore the function of Cxcl12 using our genetic model, we collaborate with the NTUH neurosurgery unit and we
generate several knockout tumor cell lines derived from Cxcl12 or Cxcr4-deficient primary astrocytes. We obtain several astrocytoma cell lines
which are either Cxcr4 knockout or Cxcl12-floxed alleles with inducible CreER driven by actin promoter. Intracranial tumor implantation model
demonstrated that astrocytoma deficient of Cxcr4 has smooth and fibrotic borders. Upon the vascularstatic drug avastin treatment, the Cxcr4
knockout tumor did not develop significant distant invasion while the Cxcr4-proficient tumor cells had prominent distant invasion. Compared to
the wildtype, Cxcr4 knockout glioma has significant intra-tumor hypoxia despite they have normal or above-normal vascular density. The vascular
phenotype is similar when we examined the Cxcl12-deficient astrocytoma. Moreover, Cxcl12-deficient astrocytoma grew slower than the wildtype
ones. The results were published in the international conference poster format.
The project is one of the executing 2015 MOST project: 驅化因子受體 CXCR4 對於阻止 bevacizumab 誘發的神經膠細胞瘤侵犯性增加之分子
機制探討與治療策略
C. Murine models of leukemogenesis
Acute myelogenous leukemia (AML) is an unique entity in the hematopoietic malignancies; it is a classic example of the multi-gene, multistep
cellular transformation and involves altered cell differentiation, proliferation and epigenetic regulation. We are interesting in the genes that are
mutated or overexpressed in the leukemia patient. In recent years, we are focusing on a couple of gene mutations including ASXL1 and WT1. Both
are found mutated in part of the AML patients. In collaboration with the NTUH hematology department, we developed murine model of these
mutation and the preliminary results revealed that they are involved in both the normal hematopoietic cell homeostasis and the leukemogenesis.
The findings from the WT1 mutant mice are summarized in this research proposal and we are extensively working on characterizing these mutant
mice.
The project is one of the executing 2015 MOST project: 腫瘤抑制基因 Wilms' tumor 1 鋅指結構缺損在小鼠血液系統及血癌致病機制的功能
探討
In addition, we are also interesting in the interaction of the myelodysplastic cells and its microenvironment. It is largely unknown how the
leukemic cells talk to the microenvironment. In our preliminary findings, we discovered several candidate genes overexpression in the AML
patients which are reported to be associated to the cytoskeleton rearrangement and actin polymerization. Whether they are influenced by the
extracellular-ligand stimulation (ex., the chemokine CXCL12) or they influence the cellular response to the extrinsic signals are awaited to be
discovered. To this point, we are currently working on the generation of those genetic mice models and combining our current genetic mice tools
to answer this question in vivo.