Please wait a minute...
浙江大学学报(医学版)  2022, Vol. 51 Issue (4): 491-499    DOI: 10.3724/zdxbyxb-2021-0369
综述     
T淋巴细胞体外发育方法的研究进展
李芸,陈新()
浙江大学医学院药物生物技术研究所,浙江 杭州 310030
Progress on methods of T lymphocyte development in vitro
LI Yun,CHEN Xin()
Institute of Pharmaceutical Biotechnology, Zhejiang University School of Medicine, Hangzhou 310030, China
 全文: PDF(537 KB)   HTML( 181 )
摘要:

T淋巴细胞(简称T细胞)在细胞过继免疫治疗(ACT)中发挥重要作用,利用T细胞体外发育方法可获得来源稳定且获取简便的T细胞,相比从自体或同种异体组织分离得到T细胞的传统方法更有优势。目前T细胞体外发育方法有胎儿胸腺器官培养、重组胸腺器官培养和Notch信号驱动的二维培养三种。其中胎儿胸腺器官培养操作简便,离体胸腺在体外培养即可支持T细胞分化发育至成熟,但完整的胸腺导致培养物维持时间有限、细胞收获困难;重组胸腺器官培养将各类胸腺基质细胞分散再重组构建三维培养环境,在体内外实验中均可支持T细胞成熟,但生物材料和三维环境导致培养物维持时间和细胞产量均受限;Notch信号驱动的二维培养采用人工呈递Notch信号通路配体来驱动T细胞分化发育,培养体系结构简单且稳定,但仅能支持T细胞发育至早期未成熟阶段。本文综述了上述培养方法的研究进展和不足之处,并讨论了T细胞体外发育未来发展的要求和方向,以助力ACT的推广和应用。

关键词: 胸腺T淋巴细胞体外发育细胞免疫治疗生物工程综述    
Abstract:

T lymphocytes (T cells) play an important role in adoptive cellular immunotherapy (ACT). T cells can be stably derived and easily obtained by various methods of T cell development in vitro, which have more advantages than traditional methods of T cells isolated from autologous or allogeneic tissues. At present, there are mainly three methods for T cell development in vitro: fetal thymus organ culture, recombinant thymus organ culture and two-dimensional culture driven by Notch signal. Fetal thymus organ culture is easy to operate, the isolated thymus can support T cell differentiation and development to maturity in vitro, but the intact thymus has problems of limited maintenance time and difficulty in cell harvesting. In recombinant thymic organ culture, various thymic stromal cells are dispersed and recombined to construct a three-dimensional culture environment, which can support T cell maturation in vitro and in vivo; however, biomaterials and three-dimensional environment may lead to limited culture maintenance time and cell yield. Two-dimensional culture method uses artificial presentation of Notch signaling pathway ligands to drive T cell differentiation and development; the culture architecture is simple and stable, but it can only support T cell development to the early immature stage. This article reviews the research progress of various culture methods of T cell development in vitro, and discusses the existing problems and the future development to facilitate the application of ACT.

Key words: Thymus    T lymphocyte    In vitro development    Adoptive cellular immuno-therapy    Biotechnology    Review
收稿日期: 2021-11-30 出版日期: 2022-11-16
CLC:  R318  
基金资助: 国家自然科学基金(81830073)
通讯作者: 陈新     E-mail: xinchen@zju.edu.cn
服务  
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章  
李芸
陈新

引用本文:

李芸,陈新. T淋巴细胞体外发育方法的研究进展[J]. 浙江大学学报(医学版), 2022, 51(4): 491-499.

LI Yun,CHEN Xin. Progress on methods of T lymphocyte development in vitro. J Zhejiang Univ (Med Sci), 2022, 51(4): 491-499.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2021-0369        https://www.zjujournals.com/med/CN/Y2022/V51/I4/491

1 JUNE C H , RIDDELL S R , SCHUMACHER T N . Adoptive cellular therapy: a race to the finish line[J]Sci Transl Med, 2015, 7( 280): 280ps7.
doi: 10.1126/scitranslmed.aaa3643
2 YING L , YAZDANI M , KOYA R , et al.Engineering tumor stromal mechanics for improved T cell therapy[J]Biochim Biophys Acta Gen Subj, 2022, 1866( 4): 130095.
doi: 10.1016/j.bbagen.2022.130095
3 HONDA T , ANDO M , ANDO J , et al.Sustainable tumor-suppressive effect of iPSC-derived rejuvenated T cells targeting cervical cancers[J]Mol Ther, 2020, 28( 11): 2394-2405.
doi: 10.1016/j.ymthe.2020.07.004
4 COMITO F , PAGANI R , GRILLI G , et al.Emerging novel therapeutic approaches for treatment of advanced cutaneous melanoma[J]Cancers, 2022, 14( 2): 271.
doi: 10.3390/cancers14020271
5 KASHIMA S , MAEDA T , MASUDA K , et al.Cytotoxic T lymphocytes regenerated from iPS cells have therapeutic efficacy in a patient-derived xenograft solid tumor model[J]iScience, 2020, 23( 4): 100998.
doi: 10.1016/j.isci.2020.100998
6 FREY N V , GILL S , HEXNER E O , et al.Long-term outcomes from a randomized dose optimization study of chimeric antigen receptor modified T cells in relapsed chronic lymphocytic leukemia[J]J Clin Oncol, 2020, 38( 25): 2862-2871.
doi: 10.1200/JCO.19.03237
7 GU R , LIU F , ZOU D , et al.Efficacy and safety of CD19 CAR T constructed with a new anti-CD19 chimeric antigen receptor in relapsed or refractory acute lymphoblastic leukemia[J]J Hematol Oncol, 2020, 13( 1): 122.
doi: 10.1186/s13045-020-00953-8
8 JOYCE J A , FEARON D T . T cell exclusion, immune privilege, and the tumor microenvironment[J]Science, 2015, 348( 6230): 74-80.
doi: 10.1126/science.aaa6204
9 SMIRNOV S , PETUKHOV A , LEVCHUK K , et al.Strategies to circumvent the side-effects of immunotherapy using allogeneic CAR-T cells and boost its efficacy: results of recent clinical trials[J]Front Immunol, 2021, 780145.
doi: 10.3389/fimmu.2021.780145
10 MORENO D F , CID J . Graft-versus-hast disease receptor[J]Med Clin (Bare), 2019, 152( 1): 22-28.
doi: 10.1016/j.medcli.2018.07.012
11 ABRAMSON J , ANDERSON G . Thymic epithelial cells[J]Annu Rev Immunol, 2017, 35( 1): 85-118.
doi: 10.1146/annurev-immunol-051116-052320
12 INGLESFIELD S , COSWAY E J , JENKINSON W E , et al.Rethinking thymic tolerance: lessons from mice[J]Trends Immunol, 2019, 40( 4): 279-291.
doi: 10.1016/j.it.2019.01.011
13 TAKABA H , MORISHITA Y , TOMOFUJI Y , et al.Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance[J]Cell, 2015, 163( 4): 975-987.
doi: 10.1016/j.cell.2015.10.013
14 BESNARD M , PADONOU F , PROVIN N , et al.AIRE deficiency, from preclinical models to human APECED disease[J]Dis Model Mech, 2021, 14( 2): dmm046359.
doi: 10.1242/dmm.046359
15 YAN F , MO X , LIU J , et al.Thymic function in the regulation of T cells, and molecular mechanisms underlying the modulation of cytokines and stress signaling[J]Mol Med Rep, 2017, 16( 5): 7175-7184.
doi: 10.3892/mmr.2017.7525
16 ROBINSON J H, OWEN J J. Generation of T-cell function in organ culture of foetal mouse thymus. II. mixed lymphocyte culture reactivity[J]. Clin Exp Immunol, 1977, 27(2): 322-327
17 COHEN A, LEE J W, DOSCH H M, et al. The expression of deoxyguanosine toxicity in T lymphocytes at different stages of maturation[J]. J Immunol, 1980, 125(4): 1578-1582
18 JENKINSON E J , FRANCHI L L , KINGSTON R , et al.Effect of deoxyguanosine on lymphopoiesis in the developing thymus rudimentin in vitro: application in the production of chimeric thymus rudiments[J]Eur J Immunol, 1982, 12( 7): 583-587.
doi: 10.1002/eji.1830120710
19 HAN J , ZÚÑIGA-PFLÜCKER J C . High-oxygen submersion fetal thymus organ cultures enable FOXN1-dependent and -independent support of T lymphopoiesis[J]Front Immunol, 2021, 652665.
doi: 10.3389/fimmu.2021.652665
20 NAKAYAMA Y , MASUDA Y , OHTA H , et al.Fgf21 regulates T-cell development in the neonatal and juvenile thymus[J]Sci Rep, 2017, 7( 1): 330.
doi: 10.1038/s41598-017-00349-8
21 SHEN H , YIN C , GAO Y N , et al.Recirculating Th2 cells induce severe thymic dysfunction via IL-4/STAT6 signaling pathway[J]Biochem Biophysl Res Commun, 2018, 501( 1): 320-327.
doi: 10.1016/j.bbrc.2018.05.030
22 CHUNG B , MONTEL-HAGEN A , GE S , et al.Engineering the human thymic microenvironment to support thymopoiesis in vivo[J]Stem Cells, 2014, 32( 9): 2386-2396.
doi: 10.1002/stem.1731
23 HERPPICH S , BECKSTETTE M , HUEHN J . The thymic microenvironment gradually modulates the phenotype of thymus‐homing peripheral conventional dendritic cells[J]Immun Inflam Dis, 2022, 10( 2): 175-188.
doi: 10.1002/iid3.559
24 DENG Z, LIU H, RUI J, et al. Reconstituted thymus organ culture[J]. Methods Mol Biol, 2016, 1323: 151-158
25 ANDERSON G , JENKINSON E J , MOORE N C , et al.MHC class Ⅱ-positive epithelium and mesenchyme cells are both required for T-cell development in the thymus[J]Nature, 1993, 362( 6415): 70-73.
doi: 10.1038/362070a0
26 MOHTASHAMI M , ZÚÑIGA-PFLÜCKER J C . Cutting edge: three-dimensional architecture of the thymus is required to maintain delta-like expression necessary for inducing T cell development[J]J Immunol, 2006, 176( 2): 730-734.
doi: 10.4049/jimmunol.176.2.730
27 YE W , LUO C , LI C , et al.Organoids to study immune functions, immunological diseases and immunotherapy[J]Cancer Lett, 2020, 31-40.
doi: 10.1016/j.canlet.2020.02.027
28 POZNANSKY M C , EVANS R H , FOXALL R B , et al.Efficient generation of human T cells from a tissue-engineered thymic organoid[J]Nat Biotechnol, 2000, 18( 7): 729-734.
doi: 10.1038/77288
29 BLACK J . Biologic performance of tantalum[J]Clin Mater, 1994, 16( 3): 167-173.
doi: 10.1016/0267-6605(94)90113-9
30 BOBYN J D , STACKPOOL G J , HACKING S A , et al.Characteristics of bone ingrowth and interface mechanics of a new porous tantalum biomaterial[J]J Bone Joint Surg Br, 1999, 81( 5): 907-914.
doi: 10.1302/0301-620X.81B5.0810907
31 TRUONG V X , HUN M L , LI F , et al. In situ-forming click-crosslinked gelatin based hydrogels for 3D culture of thymic epithelial cells[J]Biomater Sci, 2016, 4( 7): 1123-1131.
doi: 10.1039/C6BM00254D
32 SURAIYA A B , HUN M L , TRUONG V X , et al.Gelatin-based 3D microgels for in vitro T lineage cell generation[J]ACS Biomater Sci Eng, 2020, 6( 4): 2198-2208.
doi: 10.1021/acsbiomaterials.9b01610
33 BORTOLOMAI I , SANDRI M , DRAGHICI E , et al.Gene modification and three-dimensional scaffolds as novel tools to allow the use of postnatal thymic epithelial cells for thymus regeneration approaches[J]Stem Cells Transl Med, 2019, 8( 10): 1107-1122.
doi: 10.1002/sctm.18-0218
34 OCAMPO J S P , DE BRITO J M , CORRÊA-DE-SANTANA E , et al.Laminin-211 controls thymocyte——thymic epithelial cell interactions[J]Cell Immunol, 2008, 254( 1): 1-9.
doi: 10.1016/j.cellimm.2008.06.005
35 SHICHKIN V P , ANTICA M . Key factors for thymic function and development[J]Front Immunol, 2022, 926516.
doi: 10.3389/fimmu.2022.926516
36 BAJAJ P , SCHWELLER R M , KHADEMHOSSEINI A , et al.3D biofabrication strategies for tissue engineering and regenerative medicine[J]Annu Rev Biomed Eng, 2014, 16( 1): 247-276.
doi: 10.1146/annurev-bioeng-071813-105155
37 FAN Y , TAJIMA A , GOH S K , et al.Bioengineering thymus organoids to restore thymic function and induce donor-specific immune tolerance to allografts[J]Mol Ther, 2015, 23( 7): 1262-1277.
doi: 10.1038/mt.2015.77
38 OTT H C , MATTHIESEN T S , GOH S K , et al.Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart[J]Nat Med, 2008, 14( 2): 213-221.
doi: 10.1038/nm1684
39 CAMPINOTI S , GJINOVCI A , RAGAZZINI R , et al.Reconstitution of a functional human thymus by postnatal stromal progenitor cells and natural whole-organ scaffolds[J]Nat Commun, 2020, 11( 1): 6372.
doi: 10.1038/s41467-020-20082-7
40 ORLANDO G , SOKER S , STRATTA R J . Organ bioengineering and regeneration as the new Holy Grail for organ transplantation[J]Ann Surg, 2013, 258( 2): 221-232.
doi: 10.1097/SLA.0b013e31829c79cf
41 CARLYLE J R , MICHIE A M , FURLONGER C , et al.Identification of a novel developmental stage marking lineage commitment of progenitor thymocytes[J]J Exp Med, 1997, 186( 2): 173-182.
doi: 10.1084/jem.186.2.173
42 NAKANO T , KODAMA H , HONJO T . Generation of lymphohematopoietic cells from embryonic stem cells in culture[J]Science, 1994, 265( 5175): 1098-1101.
doi: 10.1126/science.8066449
43 NG H L , QUAIL E , CRUICKSHANK M N , et al.To be, or notch to be: mediating cell fate from embryogenesis to lymphopoiesis[J]Biomolecules, 2021, 11( 6): 849.
doi: 10.3390/biom11060849
44 MIZOGUCHI T, HANDA H, OMARU S, et al. Artificial notch signaling activation method using immobilized ligand beads[J]. Methods Mol Biol, 2022, 2472: 57-66
45 HIRANO K I , SUGANAMI A , TAMURA Y , et al.Delta-like 1 and Delta-like 4 differently require their extracellular domains for triggering Notch signaling in mice[J/OL]eLife, 2020, e50979.
doi: 10.7554/eLife.50979
46 SCHMITT T M , ZÚÑIGA-PFLÜCKER J C . Induction of T cell development from hematopoietic progenitor cells by Delta-like-1 in vitro[J]Immunity, 2002, 17( 6): 749-756.
doi: 10.1016/S1074-7613(02)00474-0
47 LA MOTTE-MOHS R N , HERER E , ZÚÑIGA-PFLÜCKER J C . Induction of T-cell development from human cord blood hematopoietic stem cells by Delta-like 1 in vitro[J]Blood, 2005, 105( 4): 1431-1439.
doi: 10.1182/blood-2004-04-1293
48 DE SMEDT M , HOEBEKE I , PLUM J . Human bone marrow CD34+ progenitor cells mature to T cells on OP9-DL1 stromal cell line without thymus microenvironment[J]Blood Cells Molecules Dis, 2004, 33( 3): 227-232.
doi: 10.1016/j.bcmd.2004.08.007
49 ANDERSON G , MOORE N C , OWEN J J T , et al.Cellular interactions in thymocyte development[J]Annu Rev Immunol, 1996, 14( 1): 73-99.
doi: 10.1146/annurev.immunol.14.1.73
50 LIND E F , PROCKOP S E , PORRITT H E , et al.Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development[J]J Exp Med, 2001, 194( 2): 127-134.
doi: 10.1084/jem.194.2.127
51 VIJAYARAGHAVAN J, OSBORNE B A. Notch and T cell function——a complex tale[J]. Adv Exp Med Biol, 2018, 1066: 339-354
52 MOHTASHAMI M , SHAH D K , KIANIZAD K , et al.Induction of T-cell development by Delta-like 4-expressing fibroblasts[J]Int Immunol, 2013, 25( 10): 601-611.
doi: 10.1093/intimm/dxt027
53 SEET C S , HE C , BETHUNE M T , et al.Generation of mature T cells from human hematopoietic stem and progenitor cells in artificial thymic organoids[J]Nat Methods, 2017, 14( 5): 521-530.
doi: 10.1038/nmeth.4237
54 MONTEL-HAGEN A , SEET C S , LI S , et al.Organoid-induced differentiation of conventional T cells from human pluripotent stem cells[J]Cell Stem Cell, 2019, 24( 3): 376-389.e8.
doi: 10.1016/j.stem.2018.12.011
55 SHARMA H , MORONI L . Recent advancements in regenerative approaches for thymus rejuvenation[J]Adv Sci, 2021, 8( 14): 2100543.
doi: 10.1002/advs.202100543
56 BOSTICARDO M , PALA F , CALZONI E , et al.Artificial thymic organoids represent a reliable tool to study T-cell differentiation in patients with severe T-cell lymphopenia[J]Blood Adv, 2020, 4( 12): 2611-2616.
doi: 10.1182/bloodadvances.2020001730
57 VARNUM-FINNEY B , WU L , YU M , et al.Immobilization of Notch ligand, Delta-1, is required for induction of Notch signaling[J]J Cell Sci, 2000, 113( 23): 4313-4318.
doi: 10.1242/jcs.113.23.4313
58 TAQVI S , DIXIT L , ROY K . Biomaterial-based notch signaling for the differentiation of hematopoietic stem cells into T cells[J]J Biomed Mater Res B Appl Biomater, 2006, 79A( 3): 689-697.
doi: 10.1002/jbm.a.30916
59 OHISHI K , VARNUM-FINNEY B , BERNSTEIN I D . Delta-1 enhances marrow and thymus repopulating ability of human CD34 +CD38 – cord blood cells[J]J Clin Invest, 2002, 110( 8): 1165-1174.
doi: 10.1172/JCI0216167
60 DALLAS M H , VARNUM-FINNEY B , MARTIN P J , et al.Enhanced T-cell reconstitution by hematopoietic progenitors expanded ex vivo using the Notch ligand Delta1[J]Blood, 2007, 109( 8): 3579-3587.
doi: 10.1182/blood-2006-08-039842
61 ZÚÑIGA-PFLÜCKER J C . T-cell development made simple[J]Nat Rev Immunol, 2004, 4( 1): 67-72.
doi: 10.1038/nri1257
62 VAN COPPERNOLLE S , VERSTICHEL G , TIMMERMANS F , et al.Functionally mature CD4 and CD8 TCRαβ cells are generated in OP9-DL1 cultures from human CD34 + hematopoietic cells[J]J Immunol, 2009, 183( 8): 4859-4870.
doi: 10.4049/jimmunol.0900714
63 GHOSH A , SMITH M , JAMES S E , et al.Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity[J]Nat Med, 2017, 23( 2): 242-249.
doi: 10.1038/nm.4258
64 YANG L , BALTIMORE D . Long-term in vivo provision of antigen-specific T cell immunity by programming hematopoietic stem cells[J]Proc Natl Acad Sci U S A, 2005, 102( 12): 4518-4523.
doi: 10.1073/pnas.0500600102
65 ZAKRZEWSKI J L , SUH D , MARKLEY J C , et al.Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors[J]Nat Biotechnol, 2008, 26( 4): 453-461.
doi: 10.1038/nbt1395
66 VIZCARDO R , RAFIQUL ISLAM S M , MAEDA T , et al.A three-dimensional thymic culture system to generate murine induced pluripotent stem cell-derived tumor antigen-specific thymic emigrants[J]J Vis Exp, 2019, 10.3791/58672.
doi: 10.3791/58672
67 OTSUKA R , WADA H , TSUJI H , et al.Efficient generation of thymic epithelium from induced pluripotent stem cells that prolongs allograft survival[J]Sci Rep, 2020, 10( 1): 224.
doi: 10.1038/s41598-019-57088-1
68 XIONG Y , LIU Y , GE J . Induction of pluripotent stem cells by reprogramming human ocular fibroblasts under xeno-free conditions[J]Arq Bras Oftalmol, 2018, 81( 5): 376-383.
doi: 10.5935/0004-2749.20180075
69 ZHANG Y X , LIU L P , LI M , et al.Development of individualized induced pluripotent stem cells from fibroblasts of keloid lesions in patients[J]Transplant Proc, 2018, 50( 9): 2868-2871.
doi: 10.1016/j.transproceed.2018.04.008
70 ZHANG Y , HU W , MA K , et al.Reprogramming of keratinocytes as donor or target cells holds great promise for cell therapy and regenerative medicine[J]Stem Cell Rev Rep, 2019, 15( 5): 680-689.
doi: 10.1007/s12015-019-09900-8
71 ISOGAI S , YAMAMOTO N , HIRAMATSU N , et al.Preparation of induced pluripotent stem cells using human peripheral blood monocytes[J]Cell Reprogram, 2018, 20( 6): 347-355.
doi: 10.1089/cell.2018.0024
72 HIRAMATSU N , YAMAMOTO N , ISOGAI S , et al.An analysis of monocytes and dendritic cells differentiated from human peripheral blood monocyte-derived induced pluripotent stem cells[J]Med Mol Morphol, 2020, 53( 2): 63-72.
doi: 10.1007/s00795-019-00231-8
73 KIM K , ZHAO R , DOI A , et al.Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells[J]Nat Biotechnol, 2011, 29( 12): 1117-1119.
doi: 10.1038/nbt.2052
74 NISHIMURA T , KANEKO S , KAWANA-TACHIKAWA A , et al.Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation[J]Cell Stem Cell, 2013, 12( 1): 114-126.
doi: 10.1016/j.stem.2012.11.002
75 MAEDA T , NAGANO S , ICHISE H , et al.Regeneration of CD8αβ T cells from T-cell-derived iPSC imparts potent tumor antigen-specific cytotoxicity[J]Cancer Res, 2016, 76( 23): 6839-6850.
doi: 10.1158/0008-5472.CAN-16-1149
76 THEMELI M , KLOSS C C , CIRIELLO G , et al.Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy[J]Nat Biotechnol, 2013, 31( 10): 928-933.
doi: 10.1038/nbt.2678
[1] 邹杰林,毛靖,石鑫. 牙髓-牙本质复合体再生的影响因素及其生物学策略[J]. 浙江大学学报(医学版), 2022, 51(3): 350-361.
[2] 孙萍萍,邹炜. 活细胞RNA成像技术及其在生物医学中应用研究进展[J]. 浙江大学学报(医学版), 2022, 51(3): 362-372.
[3] 邵玥明,荀静娜,陈军,卢洪洲. 人类免疫缺陷病毒感染早期启动抗逆转录病毒治疗的意义[J]. 浙江大学学报(医学版), 2022, 51(3): 373-379.
[4] 杨朝森,张晓明. 囊泡转运在肌萎缩侧索硬化中的作用研究进展[J]. 浙江大学学报(医学版), 2022, 51(3): 380-387.
[5] 刘志超,钱周旸,王英男,王慧明. 程序性坏死在骨关节炎病理机制和治疗中的作用[J]. 浙江大学学报(医学版), 2022, 51(2): 261-265.
[6] 李健宜,佟丹丹,林俊生. 恶性肿瘤饥饿疗法研究现状[J]. 浙江大学学报(医学版), 2022, 51(2): 241-250.
[7] 叶柏新,胡永仙,张明明,黄河. 脂质纳米粒-mRNA递送系统及其在嵌合抗原受体T细胞治疗中的应用[J]. 浙江大学学报(医学版), 2022, 51(2): 185-191.
[8] 刘娇,涂晓璇,刘璐璐,方维佳. 嵌合抗原受体T细胞治疗恶性实体瘤新进展[J]. 浙江大学学报(医学版), 2022, 51(2): 175-184.
[9] 胡珂嘉,黄玥,胡永仙,黄河. 嵌合抗原受体T细胞治疗血液系统恶性肿瘤研究进展[J]. 浙江大学学报(医学版), 2022, 51(2): 192-203.
[10] 张少琪,孙洁. 纳米药物递送系统在急性髓细胞性白血病治疗中的应用[J]. 浙江大学学报(医学版), 2022, 51(2): 233-240.
[11] 邢敬慈,揭伟. 甲基转移酶SET结构域家族及其在心血管发育和疾病中的作用[J]. 浙江大学学报(医学版), 2022, 51(2): 251-260.
[12] 汪文妮,陈超群,顾新华. 磁性纳米粒子复合支架及外加磁场影响成骨作用的研究进展[J]. 浙江大学学报(医学版), 2022, 51(1): 102-107.
[13] 边梦瑶,陈莉丽,雷利红. 慢性牙周炎与帕金森病相关性的研究进展[J]. 浙江大学学报(医学版), 2022, 51(1): 108-114.
[14] 金群,黄丽华. 神经认知障碍患者多成分运动干预的研究进展[J]. 浙江大学学报(医学版), 2022, 51(1): 38-46.
[15] 刘德坤,刘佳丽,张丹,杨雯晴. 细胞衰老与动脉粥样硬化的相关研究进展[J]. 浙江大学学报(医学版), 2022, 51(1): 95-101.