CD166 Regulates Human and Murine Hematopoietic Stem Cell Function and the Hematopoietic Niche

CD166 调节人和小鼠造血干细胞功能和造血生态位

• 批准号: 9126154
• 负责人: Melissa A Kacena
• 金额: $ 12.48万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-11 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126154
• 关键词: ALCAM gene; Activities of Daily Living; Binding; Biology; Bone Marrow; Bone Marrow Cells; CD34 gene; Cell Communication; Cell Lineage; Cell physiology; Cell surface; Cells; Clinical; Competence; Coupled; Data; ENG gene; Elements; Endosteum; Endothelial Cells; Engraftment; Goals; Health; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Research; Hematopoietic System; Hematopoietic stem cells; Home environment; Human; Immunoglobulins; Indium; Investigation; Knockout Mice; Ligands; Maintenance; Marrow; Mediating; Mesenchymal Stem Cells; Molecular; Mus; Osteoblasts; PECAM1 gene; PTPRC gene; Pathway interactions; Play; Principal Investigator; Publishing; Regulation; Research; Research Personnel; Role; SLAM protein; STAT3 gene; Signal Pathway; Stem cells; Supporting Cell; Surface; System; Testing; Time; Translating; Translational Research; Trees; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; base; bone; cell type; clinical efficacy; improved; in vitro Assay; in vivo; innovation; knockout animal; member; novel marker; promoter; receptor; reconstitution; self-renewal; stem; stem cell niche; therapeutic target

 DESCRIPTION (provided by applicant): Interactions in the niche between hematopoietic stem cells (HSC), osteoblasts (OB), mesenchymal stem cells (MSC), and endothelial cells (EC) are critical for HSC self-renewal and maintenance of the stem cell pool. However, molecules mediating these interactions are not well defined. Our published data determined that CD166, a member of the immunoglobulin superfamily, is expressed on normal murine HSC and niche OB. More recently, we determined that CD166 is also expressed on putative MSC and bone marrow (BM)-derived EC. With its homophilic cell-cell interactions, CD166 may be both ligand and receptor of HSC in their interactions with all these elements of the hematopoietic niche. We published that CD166 identifies a very small group of murine BM cells (LSKCD48-CD166+CD150+) highly enriched for HSC function. More than 90% of long-term in vivo repopulating potential of human cord blood-derived cells is restricted to CD34+CD38- Lineage- cells that coexpress CD166. Engraftment of HSC from CD166-/- mice in lethally irradiated hosts is defective and the CD166-/- niche cannot support the long-term engraftment of repopulating HSC. CD166 expression on STAT3-/- LSKCD48-CD150+ cells is significantly reduced and inhibition of STAT3 concomitantly reduces CD166 expression. Engraftment of STAT3-/- HSC is significantly suppressed in 1o and 2o recipients and STAT3 binds to the CD166 promoter suggesting that both CD166 and STAT3 are functionally coupled and involved in HSC competence. We hypothesize that CD166 is a universal functional marker required for HSC-niche interactions that support engraftment and HSC self-renewal and that CD166-mediated control of HSC self-renewal can be manipulated via signaling pathways impacted by STAT3 to enhance HSC clinical efficacy. Our two specific aims will: 1) Test the hypothesis that CD166 expression on HSC and on OB, MSC, and EC of the hematopoietic niche is required for the maintenance of stem cell function and that loss of CD166 expression on HSC or any of these cellular elements of the hematopoietic niche is detrimental to HSC function and 2) Test the hypothesis that gp130-activated STAT3 regulates CD166 expression and the engraftment of HSC, and that therapeutic targeting of CD166 expression can be translated to enhance human HSC engraftment in the setting of cord blood transplantation. The significance of this proposal is that it will examine the role of a new and unique functional marker of human and murine HSC and will investigate the impact of CD166 modulation on stem cell function. The conserved murine and human CD166 homology facilitates efficient translational investigations aimed at enhancing HSC engraftment and clinical utility. The novelty of this proposal stems from its potential to establish the functional capacity of a marker present on both murine and human HSC and on at least 3 cell types of the HN. The proposed research is innovative because it implicates STAT3 in the regulation of CD166 expression and will explore the molecular mechanism through which a new pathway involving CD166 and STAT3 controls HSC function, self-renewal, and engraftment.

 描述(申请人提供)：造血干细胞(HSC)、成骨细胞(OB)、间充质干细胞(MSC)和内皮细胞(EC)之间的相互作用对HSC的自我更新和干细胞库的维持至关重要。然而，调节这些相互作用的分子并没有得到很好的定义。我们发表的数据表明，CD166是免疫球蛋白超家族的成员，在正常小鼠的HSC和NICE OB上都有表达。最近，我们确定CD166也在可能的MSC和骨髓来源的EC上表达。CD166具有细胞与细胞间的亲和性，可能既是HSC的配体，又是HSC与所有这些造血生态位元素相互作用的受体。我们发表的CD166鉴定了一小群高度富含HSC功能的小鼠BM细胞(LSKCD48-CD166+CD150+)。超过90%的人脐血源细胞在体内的长期再繁殖能力局限于CD34+CD38-谱系-共表达CD166的细胞。CD166-/-小鼠的HSC在致死剂量照射的宿主体内的植入是有缺陷的，CD166-/-利基不能支持重新填充的HSC的长期植入。STAT3-/-LSKCD48-CD150+细胞上CD166的表达显著降低，抑制STAT3可降低CD166的表达。STAT3-/-HSC在10o和2o受体中的植入受到显著抑制，并且STAT3与CD166启动子结合，表明CD166和STAT3在功能上偶联并参与HSC的功能。我们假设CD166是支持植入和HSC自我更新的HSC-生态位相互作用所必需的通用功能标记物，CD166介导的HSC自我更新调控可以通过STAT3影响的信号通路来提高HSC的临床疗效。我们的两个具体目标将：1)检验如下假设，即维持干细胞功能需要在HSC以及造血龛的OB、MSC和EC上表达CD166，并且丢失HSC或造血龛的任何这些细胞元件上的CD166表达对HSC功能有害；2)检验gp130激活的STAT3调节CD166的表达和HSC的植入的假设，以及在脐血移植的背景下，CD166表达的治疗性靶向可以被转化为促进人HSC的植入。这项建议的意义在于，它将研究一个新的、独特的人和小鼠HSC功能标记物的作用，并将研究CD166调节对干细胞功能的影响。保守的小鼠和人类CD166同源性有助于有效的翻译研究，旨在加强HSC的植入和临床应用。这一建议的新颖性来自于它可能建立存在于小鼠和人类HSC以及至少3种HN细胞类型上的标记的功能能力。这项研究具有创新性，因为它涉及CD166表达的调控，并将探索涉及CD166和STAT3的新途径控制HSC功能、自我更新和植入的分子机制。