Niche-induced signaling in HSCP transplantation

造血干细胞移植中的生态位诱导信号。 儿童医院 项目负责人：Leslie E.Silberstein医学博士 哈佛医学院病理学教授 输血医学联合项目主任 波士顿儿童医院，布里格姆妇女医院， 达纳-法伯癌症研究所 免疫疾病研究所人类细胞治疗中心主任 造血干细胞和祖细胞(HSCP)可以被诱导离开骨髓，例如动员等 快速静脉输注时动员的造血干细胞(HSC)富集细胞群 回到骨髓并转移到血管外腔，在那里它们寄宿在专门的 利基市场。粘着斑激酶(FAK)是一种非受体蛋白酪氨酸激酶，其功能一直很好 在成纤维细胞中研究，在细胞黏附、存活和运动中发挥重要作用。我们自己的研究 而其他的研究表明，在造血细胞中，Fak也是外部/BM的关键整合因子 利基信号，如黏附分子、干细胞因子和CXCL12。由于早期胚胎致死(E.S) 在Fak‘^’小鼠中，Fak fl/fl纯合子小鼠被培育成携带有干扰素诱导的MXL-Cre转基因的纯合子Fak fl/fl小鼠。 广泛有效的基因缺失遍及整个造血系统，包括造血干细胞。条件性传真 在造血室中的缺失导致HSC群体的扩大，并具有两倍的长期增强植入，持续至少20周，例如MXL-CRE Fak缺失的表型。我们假设MXL-Cre Fak缺失的表型是由于HSCs与BM微环境之间相互作用的扰动造成的。然而，目前尚不清楚Fak信号如何影响HSC的内稳态/植入，因此提出了三个目标来探索以下非互斥的可能机制。Aim 1将确定FAK是否调节HSC的数量和功能；Aim 2将评估HSC和巢细胞中Fak失活对MxL-Cre Fak fl/fl小鼠(Mx^-Cre Fak缺失表型)的相对贡献；Aim 3将确定Fak是否调节HSC在骨髓中的分布和/或滞留。更好地了解控制HSC内环境稳定的分子途径应该会导致新的翻译方法，以促进体外扩增和提高临床相关HSCP群体的移植效率。在造血干细胞的数量和/或质量影响移植效率的环境中，尤其需要这种策略，即来自胎盘/脐带血的造血干细胞或来自 很难分离出足够数量的造血干细胞用于治疗。移植时间的改善将限制移植受者的发病率，并减少对血液产品的需要，以在移植后紧接着的时期治疗红细胞减少症。

Niche-induced signaiing in HSCP transplantation. Children's Hospital Project Leader: Leslie E. Silberstein, M.D. Professor of Pathology, Harvard Medical School Director, Joint Program in Transfusion Medicine Children's Hospital Boston, Brigham and Women's Hospital, Dana-Farber Cancer Institute Director, Center for Human Cell Therapy, Immune Disease Institute Hematopoietic stem and progenitor cells (HSCP) can be induced to leave the BM, e.g. mobilization, and such mobilized hematopoietic stem cell (HSC) enriched cell populations when infused intravenously rapidly home back to the marrow and transmigrate into the extravascular compartment where they lodge in specialized niches. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase, whose function has been well studied in fibroblasts, where it plays an important role in cell adhesion, survival and motility. Our own studies and those of others, suggest that also in hematopoietic cells Fak functions as a key integrator of external/BM niche signals such as adhesion molecules, stem cell factor and CXCL12. Due to early embryonic lethality (E.S) of Fak'^' mice, homozygous Fak fl/fl mice were bred to the IFN-inducible Mxl-Cre transgene that elicits widespread efficient gene deletion throughout the hematopoietic system, including HSCs. Conditional Fak deletion in the hematopoietic compartment results in an expanded HSC population with a two-fold, long-term enhanced engraftment of at least 20 weeks duration, e.g. Mxl-Cre Fak deleted phenotype. We hypothesize that the Mxl-Cre Fak deleted phenotype results from perturbations of the interactions between HSCs and the BM microenvironment. However, it is unclear how Fak signaling affects HSC homeostasis/engraftment and thus three aims are proposed to explore the following, non-mutually exclusive possible mechanisms. Aim 1 will determine if FAK regulates HSC number and function; Aim 2 will assess the relative contribution of Fak inactivation in HSC and niche cells to the hematopoietic phenotype of Mxl-Cre Fak fl/fl mice (Mx^-Cre Fak deleted phenotype); and Aim 3 will determine if Fak regulates HSC distribution and/or lodgement in bone marrow. A better understanding ofthe molecular pathways controlling HSC homeostasis should lead to new translational approaches to enhance ex vivo expansion and improve transplantation efficiency of clinically relevant HSCP populations. Such strategies are especially needed in settings where the quantity and/or quality of HSCs affect transplant efficiency, i.e. HSCs from placental/umbilical cord blood or HSCs from individuals in whom it is difficult to isolate adequate numbers of HSCs for therapy. Improvement in the time to engraftment would limit the morbidity of transplant recipients and diminish the need for blood products to manage cytopenias in the immediate post-transplant period.