Cord Blood Expansion Inside a Bioengineered Liver
生物工程肝脏内的脐带血扩增
基本信息
- 批准号:8703780
- 负责人:
- 金额:$ 11.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-19 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAdolescentAdultBehaviorBiliaryBiological ModelsBiomedical EngineeringBone MarrowCell CountCell CycleCell Differentiation processCell LineCellsConfocal MicroscopyCytoskeletonDevelopmentDiseaseElementsEndothelial CellsEngraftmentEnvironmentEpithelialExtracellular MatrixFetal LiverGoalsHematopoieticHematopoietic Stem Cell TransplantationHematopoietic stem cellsHepaticHepatic TissueHereditary DiseaseHumanImmuneIn VitroIndividualInfectionLaboratoriesLiverLocationLymphoidMaintenanceMalignant - descriptorMeasuresMesenchymalMethylcelluloseMusMyelogenousNon-Neoplastic Hematologic and Lymphocytic DisorderOrganoidsPatientsPhenotypePhysiologicalProbabilityRelative (related person)ResearchRiskRoleSerumSheepSignal TransductionSiteSourceSpeedStem cellsStromal CellsStructureSystemTimeTissuesTransplantationUmbilical Cord BloodWorkcancer geneticscell typeclinically relevantcytokinefetalfunctional outcomesinnovationnovelnovel strategiesprogenitorscaffoldself-renewalstem
项目摘要
DESCRIPTION (provided by applicant): Cord blood (CB) is a clinically relevant source of hematopoietic stem/progenitor cells (HSPC) to treat cancer and genetic diseases. The advantages of using CB include its ready availability, the reduced probability of transmitting vira infections, and the lower risk of inducing graft vs. host disease in HLA-mismatched recipients. Still, CB's delayed speed of engraftment, and the relatively low number of hematopoietic stem cells (HSC) per unit, limit its broader use. Despite the advancements made in CB-HSPC expansion, challenges remain regarding the ability to obtain, from a single unit, sufficient numbers of both long-and short-term repopulating cells, for treatment of an adolescent or adult patient. We have previously shown that CB-HSPC can be expanded and differentiated towards both the myeloid and lymphoid lineages, using a feeder layer of adult human bone marrow-derived stromal cells. Using this system, we optimized the initial progenitor content and cytokine concentrations, and showed that expanded cells had the ability to engraft pre-immune fetal sheep. While the absolute number of long-term engrafting HSC increased in this culture system, still, the relative percentage of these most primitive stem cells decreasd with time. Recently, we have developed three- dimensional (3-D), liver extracellular matrix (ECM)-derived scaffolds and seeded them with fetal hepatoblasts and endothelial cells. These cells engrafted in their putative native locations within the liver ECM scaffolds, and subsequently
displayed typical endothelial, hepatic, and biliary epithelial markers, thus creating a hepatic-lik tissue in vitro. It is well known that, during development, the fetal liver is the main site of HSC
expansion and differentiation. Within the fetal liver, HSC actively cycle and these cells outcompete adult HSC upon transplantation. Thus, within the hepatic tissue, cellular niches exist that promote asymmetric or symmetric self-renewal divisions, leading to maintenance or expansion of primitive HSC. In addition, the initial divisional behavior of CB-HSPC is highly dependent upon the environment. For example, the stromal cell line AFT024 and fetal hepatoblasts, both of murine origin, have been shown, in 2-D cultures, to effectively preserve the self- renewal capacity of human and mouse HSC, respectively. Therefore, we hypothesize that a functional and efficient expansion of CB-HPSC can be achieved under physiological conditions provided by the bioengineered human hepatic constructs. Our ultimate goal is to develop a novel platform for the efficient expansion of CB- HSPC using bioengineered human liver tissue. To this end, we will: 1) Determine the ability of 3-D bioengineered huma liver tissue constructs to support ex-vivo expansion of CB-derived HSPC~ and 2) Examine and define the functional outcome arising from interactions that occur between CB-HSPC and individual cellular and matrix components of the niches of the bioengineered liver tissue. Upon completion, these studies will add to the understanding of how fetal liver niches support HSC expansion, and, more importantly, will allow the development of a novel strategy to functionally expand CB-HPSC.
描述(由申请人提供):脐带血(CB)是临床相关的造血干/祖细胞(HSPC)来治疗癌症和遗传疾病的来源。使用CB的优点包括其现成可用性,传输ViRA感染的可能性降低以及在HLA不匹配的受体中诱导移植物与宿主疾病的降低风险。 尽管如此,CB的植入速度延迟,每单位造血干细胞(HSC)的数量相对较少,限制了其更广泛的使用。 尽管CB-HSPC扩展的进步取得了进步,但从单个单位获得足够数量的长期和短期重塑细胞的能力仍然存在挑战,以治疗青少年或成人患者。 我们先前已经表明,使用成年人类骨髓衍生的基质细胞的馈线层,CB-HSPC可以扩展并分化为髓样和淋巴样谱系。使用该系统,我们优化了初始祖细胞含量和细胞因子浓度,并表明扩展的细胞具有植入免疫前胎儿绵羊的能力。 尽管该培养系统的长期雕刻HSC的绝对数量仍然增加,但这些最原始的干细胞的相对百分比随时间减少。 最近,我们开发了三维(3-D),肝细胞外基质(ECM)衍生的支架,并用胎儿肝细胞和内皮细胞播种。这些细胞植入了肝ECM支架内的假定天然位置,随后
显示出典型的内皮,肝和胆道上皮标记物,从而在体外产生肝叶型组织。众所周知,在发育过程中,胎儿肝脏是HSC的主要部位
扩展和差异化。 在胎儿肝脏内,HSC在移植后积极循环,这些细胞在移植后胜过成人HSC。因此,在肝组织中,存在促进不对称或对称的自我更新分裂的细胞壁细分市场,从而导致原始HSC的维持或扩展。此外,CB-HSPC的最初部门行为高度取决于环境。例如,在二维培养物中,已经显示出基质细胞系AFT024和胎儿肝类母细胞,分别在2-D培养物中显示出有效保留人和小鼠HSC的自我更新能力。 因此,我们假设在生物工程的人肝构建体提供的生理条件下,可以实现CB-HPSC的功能有效扩展。我们的最终目标是开发一个新型的平台,以使用生物工程的人肝组织有效地扩展CB-HSPC。 为此,我们将:1)确定3-D生物工程性Huma肝组织构建体支持CB衍生的HSPC〜的Vivo扩展和2)检查并定义了CB-HSPC与单个细胞和基质成分之间的相互作用所产生的功能结果。完成后,这些研究将加深对胎儿肝壁ni的了解如何支持HSC扩展的理解,更重要的是,将允许开发一种新型策略,以在功能上扩展CB-HPSC。
项目成果
期刊论文数量(0)
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