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

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

doi:10.1016/j.apsb.2023.05.007

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

Acta Pharm Sin B. 2023 Jul;13(7):3027-3042. doi: 10.1016/j.apsb.2023.05.007. Epub 2023 May 16.

Authors

Luchen Sun¹, Nanfei Yang², Bing Chen³, Yuncheng Bei⁴, Zisheng Kang⁵, Can Zhang⁵, Nan Zhang⁶, Peipei Xu³, Wei Yang⁷, Jia Wei⁴, Jiangqiong Ke¹, Weijian Sun¹, Xiaokun Li⁸, Pingping Shen^{1

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Affiliations

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 Hematology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210093, 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 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.
⁶ Centre of Micro/Nano Manufacturing Technology (MNMT-Dublin), School of Mechanical & Materials Engineering, University College Dublin, Dublin 4, Ireland.
⁷ Department of Surgery, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁸ Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325035, China.
⁹ Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing 210008, China.
¹⁰ Shenzhen Research Institute of Nanjing University, Shenzhen 518000, China.

Abstract

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 1α,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 pro-differentiation 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.

Keywords: Acute myeloid leukemia; Combination therapy; Extracellular vesicles; Mesenchymal stem cell; Nonsteroidal VDR modulators.