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A Novel Function of Interleukin-10 Promoting Self-Renewal of Hematopoietic Stem Cells
Kang, Young-Ju,Yang, Seung-Jip,Park, Gyeongsin,Cho, Bin,Min, Chang-Ki,Kim, Tae-Yoon,Lee, Joon-Sung,Oh, Il-Hoan Wiley (John WileySons) 2007 Stem Cells Vol.25 No.7
<P>Self-renewal of hematopoietic stem cells (HSCs) is key to their reconstituting ability, but the factors regulating the process remain poorly understood. Here, we show that Interleukin-10 (IL-10), a pleiotropic immune modulating cytokine, can also play a role in regulating HSC self-renewal. First, a quantitative decrease of primitive hematopoietic cell populations, but not more matured cells, was observed in the bone marrows of IL-10 disrupted mice as determined by long-term in vitro cultures or in vivo competitive repopulation assays. In contrast, normal HSCs from 5-fluorouracil treated marrows cultured on the IL-10 secreting stroma displayed an enhanced repopulating activity compared with cells grown on control stroma, with ninefold higher numbers of donor-derived HSCs in the reconstituted recipient marrows. Moreover, limiting dilution transplantation assay demonstrated that exogenous addition of IL-10 in the stroma-free cultures of purified Lin- Sca-1+ c-kit+ cells caused three- to fourfold higher frequencies of HSCs in the 5-day short-term culture without indirect inhibitory effect of IL-10 on tumor necrosis factor-alpha or interferon-gamma secretion. Interestingly, primitive hematopoietic cells, including Lin- Sca-1+ c-kit+ or side population cells, expressed the surface receptor for IL-10, and microenvironmental production of IL-10 was sharply increased in the osteoblasts lining the trabecular regions of the radiation-stressed marrow but not in the steady-state marrows. These results show that IL-10 may be a ligand that can stimulate self-renewal of HSCs to promote their regeneration in addition to being a ligand for immune regulation. Disclosure of potential conflicts of interest is found at the end of this article.</P>
NOD/SCID 마우스 모델을 이용한 인간 제대혈 혼합이식에서의 생착 양상 분석
정양조,김동욱,조빈,강영주,박보배,김혜정,김태규,오일환 대한조혈모세포이식학회 2002 대한조혈모세포이식학회지 Vol.7 No.2
연구배경: 제대혈은 골수에 비해 많은 장점을 가지고 있음에도, 이식 후 성적에 있어 총세포수에 의해 좌우되며, 한 개의 태반으로부터 얻을 수 있는 총세포수의 한계가 있어 주로 소아에 국한되고 있다. 따라서 제대혈 응용의 확대를 위해 생착량을 늘이기 위한 방법으로 다중공여자에 의한 제대혈 혼합이식을 늘일 수 있는지 연구하기 위하여, 본 연구에서는 주조직적합성 형별로 조합된 제대혈을 NOD/ SCID 생쥐에 이식하는 방법으로, 혼합생착의 가능성을 연구하였다. 방법: 조합된 2개 공여자로부터 얻어진 제대혈들을 단일이식 및 혼합이식하여, 혼합이식된 숙주에 생착된 세포를 PCR-SSOP 방법을 사용하여 공여자 별로 추적하였다. 또한 각 공여자세포의 상대적 생착비율을 대조군인 단일제대혈 이식에서 얻어진 생착량과 비교하는 정량적 비교도 함께 하였다. 결과: 총단핵구를 혼합이식한 실험군에서는 주조직적합성의 일치도에 관계없이 한쪽공여자의 세포가 다른쪽에 비해 우세한 편향생착을 보였다. 그러나 임파구를 비롯한 Lineage 양성세포를 제거한 실험군에서는 주조직적합성의 불일치에도 불구하고 뚜렸한 생착의 공존이 관찰되었다. 결론: 본 연구는 제대혈의 생착량을 증가를 목적으로 총단핵구를 혼합이식할 경우 한쪽공여자의 세포에 의해 편중되며, 이것을 이식 후 생착과정에서의 두 종류의 세포의 경쟁에 의해 초래된다는 것을 보이고 있다. 또한 이러한 경쟁은 제대혈에 포함되어 있던 임파구들에 의한 것이며, 생착공존을 위하여는 공여자간 주조직적합성의 일치도 보다, 임파구의 제거가 더 중요하다는 것을 보여주고 있다. Background: Although umbilical cord blood (UCB) has been an attractive alternatives for bone marrow cells, application is limited to pediatric case due to limitation in total number of nucleated cells, that is a single most important factor for outcomes of UCB transplantation. Therefore, increasing overall engraftment by mixed transplantation of UCB derived from multiple donor should comprise one strategy to circumvent the posed limitation of UCB transplantation. In order to investigate the feasibility of establishing co-engraftment by multi-donor UCB cells, we carried out a xenotransaplantation study using NOD/SCID mice for systemic analysis of results on the input-based control of single unit transplantation. Methods: UCB units with various extent of HLA-matchings were co-transplanted into NOD/SCID mice along with single unit transplantation control. The relative contributions of engraftment by cells from each donor-derived were analyzed by HLA polymorphism using PCR-SSOP. Results: In all HLA-based mixed transplantation of total nucleated UCB cells, engraftment of one donor predominated over the other despite that equivalent amount of engraftments were achieved by single donor transplantation. When lineage depleted UCB units were co-transplanted, significant degree of co-engraftments were observed regardless of HLA disparity. Conclusion: Our result show that one donor cells dominate over the other in mixed UCB transplantation and that it is due to competition between donor cells during post-transplantation process. Our results suggest that immune cells contained in UCB unit mediate such competitioin and that 6 locus HLA matching would not be sufficient to prevent the competition.