Function And Mechanism Study Of Physiological And Pathological Bone Marrow Niche Regulate Hematopoietic Stem Cell

In physiological condition,the maintenance of the quiescent state of hematopoietic stem cells(HSCs)is an important mechanism to maintain the number of HSCs and stabilize the HSCs pool.Bone marrow niche are the sites which HSCs rely on to survive and perform functions,and it is also the indispensable conditions for maintaining HSCs quiescent state,especially in the development of hematopoietic process.Particularly,bone marrow niche regulates HSCs cell cycle transformation to ensure the HSCs pool reserves.The balance between the quiescent state of HSCs and its self-renewal ability is very important for the occurrence of leukemia and the maintenance of HSCs.However,the mechanism that how bone marrow niche regulates HSCs cell cycle conversion during hematopoietic development is not clear.In the pathological condition,the bone marrow niche plays an important role in the regulation of HSCs function.Once HSCs lose control,they can produce abnormal hematopoietic function and cause leukemia.Under the stress of chemotherapy drugs,the bone marrow niche was suppressed.The ability of reconstruction in HSCs was reduced,which was one of the reasons for the failure of bone marrow transplantation.It is not clear how the chemotherapy-induced bone marrow niche perturbs the HSCs reconstruction.Therefore,in this dissertation,we discuss the relationship between bone marrow niche and HSCs from two aspects:physiology and pathology.On the one hand,we regard the process of mouse hematopoietic development as the research object.With flow-cytometry,immunofluorescence and RNA-seq sequencing technology,we demonstrate that Nestin~+mesenchymal stem cells(Nes-MSCs)in bone marrow niche regulate HSCs cell cycle conversion in early stage of mouse hematopoietic development through IGF2/m TORC1 signaling pathways,aiming to maintain HSCs pool stability and reserves.On the other hand,we used N-MYC driven B acute lymphatic leukemia(B-ALL)mouse model as the research object.Under the treatment of chemotherapy-drug cytarabine(Ara-C),the chemotherapy-induced bone marrow niche formed.The bone marrow niche reduced levels of HSCs maintaining chemokines(SCF,CXCL12,ANGPT1 VCAM1,IL7),which were secreted by MSCs,leading to promote cell division and apoptosis and increase ROS levels in HSCs.This results generate the ability of hematopoiesis reconstruction lost,finally leading to bone marrow suppression.In summary,we discuss the mutual relationship between bone marrow niche and HSCs from two different perspectives.It combinates basic research and clinical problems,as well as providing a good theoretical basis for clinical treatment.