Clinical Applications of Stem Cells derived from Mobilized Peripheral Blood and Human Cord Blood

다국어 초록 (Multilingual Abstract)

Hematopoietic stem cells(HSC) have been used for curative purposes on leukemia, bone marrow aplasia(ie, aplastic anemia) and metabolic disorder. Though bone marrow has been a rich source for hematopoiesis, mobilized peripheral blood by cytokines proved efficient in terms of long term engraftment after myeloablative therapy. In fact, peripheral blood stem cell is superior shortening the period of cytopenia after myeloablative conditioning regimens(ie, Busulfan, Total Body Irradiation(TBI)) compared to using bone marrow for transplantation.
While mobilized hematopoietic stem cells are used often, the mechanisms on mobilization from bone marrow to peripheral blood are not elucidated yet. So far, important players in these processes are; 1) VLA-4/VCAM-1, LFA-1/ICAM-1, 2) SDF-1/CXCR4, 3) protease(ie, neutrophil elastase, cathepsin-G, MMP-9. The limitation of using G-CSF, which is the most popular cytokine in the clinic for HSC mobilization is as follows; 1) side effects(muscle pain, weakness and occasional leukostasis), 2) slowness(it takes 4-6 days to have optimal mobilization). In result, it is necessary to find new molecules for the shortening of optimization(ideally few hours) and molecules with minimal side effects, but at the same time providing large amount of HSC.
VE-cadherin has a role in vascular integrity among vascular endothelial cells. In our Lab, we found the decreased expression of VE-cadherin during G-CSF mobilization. When G-CSF was given with anti-VE cadherin, the speed of mobilization was faster compared to that of G-CSF alone. In vitro, the expression of BLT2 was upregulated on nucleated cells in the bone marrow when G-CSF was given. In addition, we were able to observe maximal mobilization within 4hours after an injection of LTB4 in the murine model.
In 1989, Gluckman et al found that human cord blood(HCB) was a rich source of HSC and HCB was used for an allo-graft after a conditioning regimen for a Fanconi anemia patient. More than 15 years later, this patient is still in complete remission maintaining allo-graft. In addition, HCB has many attractions; 1) readily available, 2) less exposed to infective organisms, 3) more primitive nature, 4) less GVHD(Graft Versus Host Disease) after allogeneic transplantation. But HCB has a critical limitation, which is a low number of HSC in HCB for transplantation in adult patients.
In the midst of developing an effective ex-vivo expansion system of HCB, we found that Hyaluronic acid(HA), ligand of CD44, had a ability for expanding more cells but at the same time, we found more apoptosis during this process. The methodes for maintaining sternness of HSC but minimizing apoptosis is being investigated during ex-vivo expansion system. Meanwhile, we are also trying to develop better ways for inducing early and late endothelial progenitor cells which can be used for angiogenesis and myogenesis using different cytokines and from different graft sources including HCB.
By understanding the mechanisms of the mobilization of HSC in depth, we will have a large amount of HSC and at the same time a speedy way to mobilize HSC. Doing that, we will be in a good position in graft engineering for cell therapies. In addition, via an effective and smart exvivo expansion system on HCB, we are able to provide more relevant cells for the purposes on tissue repair.