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中华细胞与干细胞杂志(电子版) ›› 2024, Vol. 14 ›› Issue (02) : 122 -127. doi: 10.3877/cma.j.issn.2095-1221.2024.02.008

综述

造血干/祖细胞体外扩增和临床应用
张一健1, 赵龙2, 杨扬2, 张贝贝2, 张译予2, 张斌2,()   
  1. 1. 100071 北京,安徽医科大学解放军307临床学院;100071 北京,中国人民解放军总医院第五医学中心血液病医学部;100071 北京,造血干细胞治疗及转化研究北京市重点实验室
    2. 100071 北京,中国人民解放军总医院第五医学中心血液病医学部;100071 北京,造血干细胞治疗及转化研究北京市重点实验室
  • 收稿日期:2023-11-24 出版日期:2024-04-01
  • 通信作者: 张斌
  • 基金资助:
    国家自然科学基金青年科学基金(31900678); 北京市科学技术委员会干细胞与再生医学研究项目(Z181100001818004); 安徽医科大学研究生科研与实践创新项目(YJS20230210)

Expansion ex vivo and clinical applications of hematopoietic stem/progenitor cells

Yijian Zhang 1, Long Zhao2, Yang Yang2, Beibei Zhang2, Yiyu Zhang2, Bin Zhang2,()   

  1. 1. Anhui Medical University PLA 307 Clinical College, Beijing 100071, China; Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing 100071, China; Beijing Key Laboratory of Hematopoietic Stem Cell Therapy and Transformation Research, Beijing 100071, China
    2. Senior Department of Hematology, the Fifth Medical Center of PLA General Hospital, Beijing 100071, China; Beijing Key Laboratory of Hematopoietic Stem Cell Therapy and Transformation Research, Beijing 100071, China
  • Received:2023-11-24 Published:2024-04-01
  • Corresponding author: Bin Zhang
引用本文:

张一健, 赵龙, 杨扬, 张贝贝, 张译予, 张斌. 造血干/祖细胞体外扩增和临床应用[J]. 中华细胞与干细胞杂志(电子版), 2024, 14(02): 122-127.

Yijian Zhang , Long Zhao, Yang Yang, Beibei Zhang, Yiyu Zhang, Bin Zhang. Expansion ex vivo and clinical applications of hematopoietic stem/progenitor cells[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2024, 14(02): 122-127.

造血干细胞(HSC)处于血细胞谱系顶端,维持机体正常造血稳态与免疫功能。HSC移植(HSCT)的临床应用为恶性血液系统疾病提供治愈可能,也是未来基因疗法的理想靶细胞。HSCT部分供者动员不良、脐带血来源HSC多向分化能力良好但数量少等问题是HSC治疗发展的瓶颈。真正意义的HSC体外分离仍存在技术瓶颈,目前仅能高效分离出造血干/ 祖细胞(HSPC),通过添加细胞因子、小分子化合物和模拟HSC生存环境(骨髓生态位)以及基因编辑干预进行HSPC体外培养扩增,进而实现HSC的数量增加满足临床需求。高效安全的HSPC体外扩增将推进临床移植应用发展,对治愈血液疾病和提供足够数量HSC用于基因治疗具有重要意义。

Hematopoietic stem cells (HSC) are at the top of the blood cell lineage and maintain normal hematopoietic homeostasis and immune function. The clinical application of hematopoietic stem cell transplantation (HSCT) provides the possibility of curing malignant hematological diseases, and it is also an ideal target cell for future gene therapy. There are many challenges with the development of HSC therapy, including poor mobilization of HSCT donors and a limited number of cord blood-derived HSCs. At present, there are still technical challenges in the isolation of HSC ex vivo. Only hematopoietic stem/progenitor cells (HSPC) can be efficiently isolated. HSPC can be expanded ex vivo by adding cytokines, small molecular compounds, simulating HSC survival environment (bone marrow niche) and gene editing intervention, so as to increase the number of HSC to meet clinical needs. Efficient and safe expansion of HSPC ex vivo will promote the development of clinical transplantation applications, which is of great significance for curing blood diseases and providing sufficient number of HSC for gene therapy.

图1 造血干细胞体外扩增优化策略注:图1a为添加造血细胞因子,SCF为干细胞因子、FLT3-L为酪氨酸激酶3配体、TPO为血小板生成素、FGF为成纤维细胞生长因子、IL-3为白介素-3、IL-6为白介素-6、ANGPTLs为血管生成素样蛋白、TNFSF15为肿瘤坏死因子超家族成员;图1b为添加化合物,NAM为烟酰胺、PVA为聚乙酸乙烯酯、TEPA为四乙烯五胺;图1c为模拟骨髓生态位:Fibroblasts为成纤维细胞、Nerve fiber为神经纤维、Macrophages为巨噬细胞、Endothelial cells为内皮细胞、Dendritic cells为树突状细胞、MSC为间充质干细胞、Niche为骨髓龛;图1d为基因编辑调控
图2 造血干细胞体外扩增后临床应用注:HSC为造血干细胞
1
Charlesworth CT, Hsu I, Wilkinson AC, et al. Immunological barriers to haematopoietic stem cell gene therapy[J]. Nat Rev Immunol, 2022, 22(12):719-733.
2
Ferrari S, Valeri E, Conti A, et al. Genetic engineering meets hematopoietic stem cell biology for next-generation gene therapy[J]. Cell Stem Cell, 2023, 30(5):549-570.
3
Abraham AA, Tisdale JF. Gene therapy for sickle cell disease: moving from the bench to the bedside[J]. Blood, 2021, 138(11):932-941.
4
Wilkinson AC, Igarashi KJ, Nakauchi H. Haematopoietic stem cell self-renewal in vivo and ex vivo[J]. Nat Rev Genet, 2020, 21(9):541-554.
5
Becker HJ, Ishida R, Wilkinson AC, et al. Controlling genetic heterogeneity in gene-edited hematopoietic stem cells by single-cell expansion[J]. Cell Stem Cell, 2023, 30(7):987-1000.
6
Omatsu Y. Cellular niches for hematopoietic stem cells in bone marrow under normal and malignant conditions[J]. Inflamm Regen, 2023, 43(1):15.
7
Zhang X, Cao D, Xu L, et al. Harnessing matrix stiffness to engineer a bone marrow niche for hematopoietic stem cell rejuvenation[J]. Cell Stem Cell, 2023, 30(4):378-395.
8
Kandarakov O, Belyavsky A, Semenova E. Bone marrow niches of hematopoietic stem and progenitor cells[J]. Int J Mol Sci, 2022, 23(8):4462.
9
Mayani H, Lansdorp PM. Biology of human umbilical cord blood- derived hematopoietic stem/progenitor cells[J]. Stem Cells, 1998, 16(3):153-165.
10
Sakurai M, Ishitsuka K, Ito R, et al. Chemically defined cytokine- free expansion of human haematopoietic stem cells[J]. Nature, 2023, 615(7950):127-133.
11
Ku H, Yonemura Y, Kaushansky K, et al. Thrombopoietin, the ligand for the Mpl receptor, synergizes with steel factor and other early acting cytokines in supporting proliferation of primitive hematopoietic progenitors of mice[J]. Blood, 1996, 87(11):4544-4551.
12
Flores-Guzman P, Fernandez-Sanchez V, Valencia-Plata I, et al. Comparative in vitro analysis of different hematopoietic cell populations from human cord blood: in search of the best option for clinically oriented ex vivo cell expansion[J]. Transfusion, 2013, 53(3):668-678.
13
Yeoh JS, van Os R, Weersing E, et al. Fibroblast growth factor-1 and -2 preserve long-term repopulating ability of hematopoietic stem cells in serum-free cultures[J]. Stem Cells, 2006, 24(6):1564-1572.
14
Weinreich MA, Lintmaer I, Wang L, et al. Growth factor receptors as regulators of hematopoiesis[J]. Blood, 2006, 108(12):3713-3721.
15
Zhang CC, Kaba M, Ge G, et al. Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells[J]. Nat Med, 2006, 12(2):240-245.
16
North TE, Goessling W, Walkley CR, et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis[J]. Nature, 2007, 447(7147):1007-1011.
17
Ding Y, Gao S, Shen J, et al. TNFSF15 facilitates human umbilical cord blood haematopoietic stem cell expansion by activating notch signal pathway[J]. J Cell Mol Med, 2020, 24(19):11146-11157.
18
Boitano AE, Wang J, Romeo R, et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells[J]. Science, 2010, 329(5997):1345-1348.
19
Wagner JJ, Brunstein CG, Boitano AE, et al. Phase Ⅰ/Ⅱ trial of stemRegenin-1 expanded umbilical cord blood hematopoietic stem cells supports testing as a stand-alone graft[J]. Cell Stem Cell, 2016, 18(1):144-155.
20
Tao L, Togarrati PP, Choi KD, et al. StemRegenin 1 selectively promotes expansion of multipotent hematopoietic progenitors derived from human embryonic stem cells[J]. J Stem Cells Regen Med, 2017, 13(2):75-79.
21
Fares I, Chagraoui J, Gareau Y, et al. Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal[J]. Science, 2014, 345(6203):1509-1512.
22
Wen R, Dong C, Xu C, et al. UM171 promotes expansion of autologous peripheral blood hematopoietic stem cells from poorly mobilizing lymphoma patients[J]. Int Immunopharmacol, 2020, 81:106266.
23
Cohen S, Roy J, Lachance S, et al. Hematopoietic stem cell transplantation using single UM171-expanded cord blood: a single- arm, phase 1-2 safety and feasibility study[J]. Lancet Haematol, 2020, 7(2):e134-e145.
24
Subramaniam A, Žemaitis K, Talkhoncheh MS, et al. Lysine-specific demethylase 1A restricts ex vivo propagation of human HSCs and is a target of UM171[J]. Blood, 2020, 136(19):2151-2161.
25
He M, Xu H, Liu G, et al. Levistilide a promotes expansion of human umbilical cord blood hematopoietic stem cells by enhancing antioxidant activity[J]. Front Pharmacol, 2022, 13:806837.
26
Peled T, Shoham H, Aschengrau D, et al. Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment[J]. Exp Hematol, 2012, 40(4):342-355.
27
Horwitz ME, Wease S, Blackwell B, et al. Phase Ⅰ/Ⅱ study of stem-cell transplantation using a single cord blood unit expanded ex vivo with nicotinamide[J]. J Clin Oncol, 2019, 37(5):367-374.
28
Horwitz ME, Stiff PJ, Cutler C, et al. Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study[J]. Blood, 2021, 138(16):1429-1440.
29
Wilkinson AC, Ishida R, Kikuchi M, et al. Long-term ex vivo haematopoietic-stem-cell expansion allows nonconditioned transplantation[J]. Nature, 2019, 571(7763):117-121.
30
Albayrak E, Uslu M, Akgol S, et al. Small molecule-mediated modulation of ubiquitination and neddylation improves HSC function ex vivo[J]. J Cell Physiol, 2021, 236(12):8122-8136.
31
Gao Y, Yang P, Shen H, et al. Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells[J]. Nat Commun, 2015, 6:6328.
32
Li Y, Zhang W, Zhang Y, et al. Enhanced self-renewal of human long-term hematopoietic stem cells by a sulfamoyl benzoate derivative targeting p18INK4C[J]. Blood Adv, 2021, 5(17):3362-3372.
33
Peled T, Mandel J, Goudsmid RN, et al. Pre-clinical development of cord blood-derived progenitor cell graft expanded ex vivo with cytokines and the polyamine copper chelator tetraethylenepentamine[J]. Cytotherapy, 2004, 6(4):344-355.
34
Stiff PJ, Montesinos P, Peled T, et al. Cohort-controlled comparison of umbilical cord blood transplantation using carlecortemcel-L, a single progenitor-enriched cord blood, to double cord blood unit transplantation[J]. Biol Blood Marrow Transplant, 2018, 24(7):1463-1470.
35
Kumar S, Geiger H. HSC niche biology and HSC expansion ex vivo[J]. Trends Mol Med, 2017, 23(9):799-819.
36
Butler JM, Nolan D J, Vertes EL, et al. Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells[J]. Cell Stem Cell, 2010, 6(3):251-264.
37
李猛, 盛宏霞, 刘阳, 等. 脐带间充质干细胞联合UM171对脐血源CD34(+)细胞的扩增效果研究[J/CD]. 中华细胞与干细胞杂志(电子版), 2017,7(2):93-100.
38
Nakahara F, Borger DK, Wei Q, et al. Engineering a haematopoietic stem cell niche by revitalizing mesenchymal stromal cells[J]. Nat Cell Biol, 2019, 21(5):560-567.
39
Bai T, Li J, Sinclair A, et al. Expansion of primitive human hematopoietic stem cells by culture in a zwitterionic hydrogel[J]. Nat Med, 2019, 25(10):1566-1575.
40
Umemoto T, Yamato M, Ishihara J, et al. Integrin-αvβ3 regulates thrombopoietin-mediated maintenance of hematopoietic stem cells[J]. Blood, 2012,119(1):83-94.
41
Wang X, Broxmeyer HE. DUSP16 is a regulator of human hematopoietic stem and progenitor cells and promotes their expansion ex vivo[J]. Leukemia, 2021, 35(5):1516-1520.
42
Li C, Wu B, Li Y, et al. Loss of sphingosine kinase 2 promotes the expansion of hematopoietic stem cells by improving their metabolic fitness[J]. Blood, 2022,140(15):1686-1701.
43
Breda L, Papp TE, Triebwasser MP, et al. In vivo hematopoietic stem cell modification by mRNA delivery[J]. Science, 2023,381(6656):436-443.
44
McDermott DH, Velez D, Cho E, et al. A phase Ⅲ randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome[J]. J Clin Invest, 2023,133(19):e164918.
45
Karres D, Ali S, van Hennik PB, et al. EMA recommendation for the pediatric indications of plerixafor (Mozobil) to enhance mobilization of hematopoietic stem cells for collection and subsequent autologous transplantation in children with lymphoma or malignant solid tumors[J]. Oncologist, 2020, 25(6):e976-e981.
46
Sureda A, Chabannon C, Masszi T, et al. Analysis of data collected in the European Society for Blood and Marrow Transplantation (EBMT) Registry on a cohort of lymphoma patients receiving plerixafor[J]. Bone Marrow Transplant, 2020, 55(3):613-622.
47
Crees ZD, Rettig MP, Jayasinghe RG, et al. Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma:a randomized phase 3 trial[J]. Nat Med, 2023, 29(4):869-879.
48
Broxmeyer HE, Luchsinger LL, Weinberg RS, et al. Insights into highly engraftable hematopoietic cells from 27-year cryopreserved umbilical cord blood[J]. Cell Rep Med, 2023:101259.
49
Zhu X, Tang B, Sun Z. Umbilical cord blood transplantation: Still growing and improving[J]. Stem Cells Transl Med, 2021, 10 Suppl 2(Suppl 2):S62-S74.
50
Kok LMC, Bungener L, de Bock GH, et al. Risk factors associated with the development of moderate to severe chronic graft-versus-host disease after non-myeloablative conditioning allogeneic stem cell transplantation in patients with AML or MDS[J]. Hum Cell, 2020,33(1):243-251.
51
Keret S, Zuckerman T, Henig I, et al. Complete resolution of gastric antral vascular ectasia after autologous haematopoietic stem cell transplantation in systemic sclerosis[J]. Ann Rheum Dis, 2023, 82(7):995-996.
52
Peviani M, Das S, Patel J, et al. An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model[J]. EMBO Mol Med, 2023, 15(4):e15968.
53
Li YR, Zhou Y, Kim YJ, et al. Development of allogeneic HSC- engineered iNKT cells for off-the-shelf cancer immunotherapy[J]. Cell Rep Med, 2021, 2(11):100449.
54
Wu Y, Zeng J, Roscoe BP, et al. Highly efficient therapeutic gene editing of human hematopoietic stem cells[J]. Nat Med, 2019, 25(5):776-783.
55
Xu L, Wang J, Liu Y, et al. CRISPR-edited stem cells in a patient with HIV and acute lymphocytic leukemia[J]. N Engl J Med, 2019, 381(13):1240-1247.
56
Newby GA, Yen JS, Woodard KJ, et al. Base editing of haematopoietic stem cells rescues sickle cell disease in mice[J]. Nature, 2021, 595(7866):295-302.
57
Capo V, Penna S, Merelli I, et al. Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis[J]. Haematologica, 2021, 106(1):74-86.
58
Jaiswal S, Libby P. Clonal haematopoiesis:connecting ageing and inflammation in cardiovascular disease[J]. Nat Rev Cardiol, 2020, 17(3):137-144.
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