A novel mesenchymal stem cell-based regimen for acute myeloid leukemia differentiation therapy  

作　　者：Luchen Sun Nanfei Yang Bing Chen Yuncheng Bei Zisheng Kang Can Zhang Nan Zhang Peipei Xu Wei Yang Jia Wei Jiangqiong Ke Weijian Sun Xiaokun Li Pingping Shen 

机构地区：[1]The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University,Wenzhou 325027,China [2]School of Pharmaceutical Science,Wenzhou Medical University,Wenzhou 325035,China [3]Department of Urology,Drum Tower Hospital,Medical School of Nanjing University,Institute of Urology,Nanjing University,Nanjing 210008,China [4]The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital,the Affiliated Hospital of Nanjing University Medical School,Nanjing University,Nanjing 210008,China [5]Department of Hematology,the Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing 210093,China [6]State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases,Center of Drug Discovery,China Pharmaceutical University,Nanjing 210009,China [7]Centre of Micro/Nano Manufacturing Technology(MNMT-Dublin),School of Mechanical&Materials Engineering,University College Dublin,Dublin 4,Ireland [8]Department of Surgery,Division of Cancer Biology and Therapeutics,Cedars-Sinai Medical Center,Los Angeles,CA 90048,USA [9]Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine,Vision and Brain Health)&School of Pharmaceutical Science,Wenzhou Medical University,Wenzhou 325035,China [10]Shenzhen Research Institute of Nanjing University,Shenzhen 518000,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第7期3027-3042,共16页药学学报（英文版）

基　　金：supported by grants from the Natural Science Foundation of Jiangsu Province(BK20222009,China);Guangdong Basic and Applied Basic Research Foundation(2021B1515120016,China);National Natural Science Foundation of China(81972261);China Postdoctoral Science Foundation(2022M712436);Zhejiang Provincial Natural Science Foundation of China under Grant No.LQ23H070001。

摘　　要：Currently the main treatment of acute myeloid leukemia(AML)is chemotherapy combining hematopoietic stem cell transplantation.However,the unbearable side effect of chemotherapy and the high risk of life-threatening infections and disease relapse following hematopoietic stem cell transplantation restrict its application in clinical practice.Thus,there is an urgent need to develop alternative therapeutic tactics with significant efficacy and attenuated adverse effects.Here,we revealed that umbilical cord-derived mesenchymal stem cells(UC-MSC)efficiently induced AML cell differentiation by shuttling the neutrophil elastase(NE)-packaged extracellular vesicles(EVs)into AML cells.Interestingly,the generation and release of NE-packaged EVs could be dramatically increased by vitamin D receptor(VDR)activation in UC-MSC.Chemical activation of VDR by using its agonist 1a,25-dihydroxyvitamin D3 efficiently enhanced the pro-differentiation capacity of UC-MSC and then alleviated malignant burden in AML mouse model.Based on these discoveries,to evade the risk of hypercalcemia,we synthetized and identified sw-22,a novel non-steroidal VDR agonist,which exerted a synergistic prodifferentiation function with UC-MSC on mitigating the progress of AML.Collectively,our findings provided a non-gene editing MSC-based therapeutic regimen to overcome the differentiation blockade in AML.

关 键 词：Mesenchymal stem cell Acute myeloid leukemia Extracellular vesicles Nonsteroidal VDR modulators Combination therapy 

分 类 号：R733.71[医药卫生—肿瘤]