Clodronate Improves Survival of Transplanted Hoxb8 Myeloid Progenitors with Constitutively Active GMCSFR in Immunocompetent Mice.
Clodronate Improves Survival of Transplanted Hoxb8 Myeloid Progenitors with Constitutively Active GMCSFR in Immunocompetent Mice.
复制标题
DOI：
10.1016/j.omtm.2017.08.007
复制
发表时间：
2017-12-15
期刊：
影响因子：
--
通讯作者：
Szoka FC
中科院分区：
文献类型：
--
作者：
Lee S;Kivimäe S;Szoka FC
通过维持Hoxb8转录因子活性来产生大量髓系祖细胞，巨噬细胞的前体（MΦs）的新方法重新激发了人们对MΦ细胞疗法的兴趣。我们通过转导具有组成性表达Hoxb8和loxP的谱系阴性骨髓细胞，生成了依赖Hoxb8的髓系祖细胞（hdp）。当Hoxb8被他莫昔芬诱导的Cre去除时，HDPs无限增殖并分化为MΦ。我们用组成活性GMCSF受体和他莫昔芬诱导的转录因子IRF8对hdp进行了基因修饰，我们将其称为“HDP-on”。HDP-on在没有GMCSF的情况下增殖，并在暴露于他莫昔芬和ruxolitinib（通过JAK1/2阻断的GMCSF抑制剂）时分化为MΦ。利用荧光素酶报告基因，定量测定免疫缺陷NCG小鼠腹腔注射hdp的生物分布；在腹腔、肝、脾、肾、骨髓、脑、肺、心脏和血液中检测到14天的HDPs。在免疫能力强的BALB/c小鼠中，移植后1天腹腔内检测到HDP-on细胞，但未检测到hdp。用氯膦酸脂质体预处理BALB/c小鼠，可显著提高第7天腹腔、脾脏和肝脏中HDPs和HDP-on细胞的存活率，但第14天无法检测到细胞。使用HDP-on和氯膦酸脂质体可显著提高hdp移植后的短期生存率，为MΦ-based治疗开辟了道路。
New methods to produce large numbers of myeloid progenitor cells, precursors to macrophages (MΦs), by maintaining Hoxb8 transcription factor activity has reinvigorated interest in MΦ cell therapies. We generated Hoxb8-dependent myeloid progenitors (HDPs) by transducing lineage-negative bone marrow cells with a constitutively expressed Hoxb8 flanked by loxP. HDPs proliferate indefinitely and differentiate into MΦ when Hoxb8 is removed by a tamoxifen-inducible Cre. We genetically modified HDPs with a constitutively active GMCSF receptor and the tamoxifen-induced transcription factor IRF8, which we have termed “HDP-on.” The HDP-on proliferates without GMCSF and differentiates into the MΦ upon exposure to tamoxifen and ruxolitinib (GMCSF inhibitor via JAK1/2 blockade). We quantified the biodistribution of HDPs transplanted via intraperitoneal injection into immunodeficient NCG mice with a luciferase reporter; HDPs are detected for 14 days in the peritoneal cavity, liver, spleen, kidney, bone marrow, brain, lung, heart, and blood. In immunocompetent BALB/c mice, HDP-on cells, but not HDPs, are detected 1 day post-transplantation in the peritoneal cavity. Pretreatment of BALB/c mice with liposomal clodronate significantly enhances survival at day 7 for HDPs and HDP-on cells in the peritoneal cavity, spleen, and liver, but cells are undetectable at day 14. Short-term post-transplantation survival of HDPs is significantly improved using HDP-on and liposomal clodronate, opening a path for MΦ-based therapeutics.
登录
查看更多内容
影响因子：
4.8
作者：
Ansari, Amir Mehdi;Ahmed, A. Karim;Matsangos, Aerielle E.;Lay, Frank;Born, Louis J.;Marti, Guy;Harmon, John W.;Sun, Zhaoli
通讯作者：
Sun, Zhaoli
影响因子：
64.5
作者：
Haldar M;Kohyama M;So AY;Kc W;Wu X;Briseño CG;Satpathy AT;Kretzer NM;Arase H;Rajasekaran NS;Wang L;Egawa T;Igarashi K;Baltimore D;Murphy TL;Murphy KM
通讯作者：
Murphy KM
影响因子：
5
作者：
Bressani RF;Nowacek AS;Singh S;Balkundi S;Rabinow B;McMillan J;Gendelman HE;Kanmogne GD
通讯作者：
Kanmogne GD
DOI：
10.1016/j.jconrel.2016.07.018
发表时间：
2016-10-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Lee S;Kivimäe S;Dolor A;Szoka FC
通讯作者：
Szoka FC
影响因子：
5.2
作者：
Huber, Bruno C.;Ransohoff, Julia D.;Ransohoff, Katherine J.;Riegler, Johannes;Ebert, Antje;Kodo, Kazuki;Gong, Yongquan;Sanchez-Freire, Veronica;Dey, Devaveena;Kooreman, Nigel G.;Diecke, Sebastian;Zhang, Wendy Y.;Odegaard, Justin;Hu, Shijun;Gold, Joseph D.;Robbins, Robert C.;Wu, Joseph C.
通讯作者：
Wu, Joseph C.