Molecules and Cells

  • 제45권7호
  • /
  • Pages.479-494
  • /
  • 2022
  • /
  • 1016-8478(pISSN)
  • /
  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
권호 표지
DOI QR코드

DOI QR Code

Improving the Safety of Mesenchymal Stem Cell-Based Ex Vivo Therapy Using Herpes Simplex Virus Thymidine Kinase

  • 투고 : 2021.11.08
  • 심사 : 2021.12.16
  • 발행 : 2022.07.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Human mesenchymal stem cells (MSCs) are multipotent stem cells that have been intensively studied as therapeutic tools for a variety of disorders. To enhance the efficacy of MSCs, therapeutic genes are introduced using retroviral and lentiviral vectors. However, serious adverse events (SAEs) such as tumorigenesis can be induced by insertional mutagenesis. We generated lentiviral vectors encoding the wild-type herpes simplex virus thymidine kinase (HSV-TK) gene and a gene containing a point mutation that results in an alanine to histidine substitution at residue 168 (TK(A168H)) and transduced expression in MSCs (MSC-TK and MSC-TK(A168H)). Transduction of lentiviral vectors encoding the TK(A168H) mutant did not alter the proliferation capacity, mesodermal differentiation potential, or surface antigenicity of MSCs. The MSC-TK(A168H) cells were genetically stable, as shown by karyotyping. MSC-TK(A168H) responded to ganciclovir (GCV) with an half maximal inhibitory concentration (IC50) value 10-fold less than that of MSC-TK. Because MSC-TK(A168H) cells were found to be non-tumorigenic, a U87-TK(A168H) subcutaneous tumor was used as a SAE-like condition and we evaluated the effect of valganciclovir (vGCV), an oral prodrug for GCV. U87-TK(A168H) tumors were more efficiently ablated by 200 mg/kg vGCV than U87-TK tumors. These results indicate that MSC-TK(A168H) cells appear to be pre-clinically safe for therapeutic use. We propose that genetic modification with HSV-TK(A168H) makes allogeneic MSC-based ex vivo therapy safer by eliminating transplanted cells during SAEs such as uncontrolled cell proliferation.

키워드

과제정보

This research was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (HI20C0457 to H.S.K.), the Ministry of Food and Drug Safety in 2021 (18172MFDS182-5 to H.S.K.) and the Technology development Program (S3030270 to D.Y.C.) funded by the Ministry of SMEs and Startups (MSS, Korea).

참고문헌

  1. al-Shawi, R., Burke, J., Wallace, H., Jones, C., Harrison, S., Buxton, D., Maley, S., Chandley, A., and Bishop, J.O. (1991). The herpes simplex virus type 1 thymidine kinase is expressed in the testes of transgenic mice under the control of a cryptic promoter. Mol. Cell. Biol. 11, 4207-4216. https://doi.org/10.1128/MCB.11.8.4207
  2. Aurich, H., Sgodda, M., Kaltwasser, P., Vetter, M., Weise, A., Liehr, T., Brulport, M., Hengstler, J.G., Dollinger, M.M., Fleig, W.E., et al. (2009). Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo. Gut 58, 570-581. https://doi.org/10.1136/gut.2008.154880
  3. Balzarini, J., Liekens, S., Solaroli, N., El Omari, K., Stammers, D.K., and Karlsson, A. (2006). Engineering of a single conserved amino acid residue of herpes simplex virus type 1 thymidine kinase allows a predominant shift from pyrimidine to purine nucleoside phosphorylation. J. Biol. Chem. 281, 19273-19279. https://doi.org/10.1074/jbc.M600414200
  4. Belizario, J.E. (2009). Immunodeficient mouse models: an overview. Open Immunol. J. 2, 79-85. https://doi.org/10.2174/1874226200902010079
  5. Beltinger, C., Fulda, S., Kammertoens, T., Meyer, E., Uckert, W., and Debatin, K.M. (1999). Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases. Proc. Natl. Acad. Sci. U. S. A. 96, 8699-8704. https://doi.org/10.1073/pnas.96.15.8699
  6. Black, M.E., Kokoris, M.S., and Sabo, P. (2001). Herpes simplex virus-1 thymidine kinase mutants created by semi-random sequence mutagenesis improve prodrug-mediated tumor cell killing. Cancer Res. 61, 3022-3026.
  7. Black, M.E., Newcomb, T.G., Wilson, H.M., and Loeb, L.A. (1996). Creation of drug-specific herpes simplex virus type 1 thymidine kinase mutants for gene therapy. Proc. Natl. Acad. Sci. U. S. A. 93, 3525-3529. https://doi.org/10.1073/pnas.93.8.3525
  8. Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C.C., Veres, G., Schmidt, M., Kutschera, I., Vidaud, M., Abel, U., Dal-Cortivo, L., Caccavelli, L., et al. (2009). Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326, 818-823. https://doi.org/10.1126/science.1171242
  9. Cen, S., Li, J., Cai, Z., Pan, Y., Sun, Z., Li, Z., Ye, G., Zheng, G., Li, M., Liu, W., et al. (2020). TRAF4 acts as a fate checkpoint to regulate the adipogenic differentiation of MSCs by activating PKM2. EBioMedicine 54, 102722. https://doi.org/10.1016/j.ebiom.2020.102722
  10. Chang, D.Y., Jung, J.H., Kim, A.A., Marasini, S., Lee, Y.J., Paek, S.H., Kim, S.S., and Suh-Kim, H. (2020). Combined effects of mesenchymal stem cells carrying cytosine deaminase gene with 5-fluorocytosine and temozolomide in orthotopic glioma model. Am. J. Cancer Res. 10, 1429-1441.
  11. Chang, D.Y., Yoo, S.W., Hong, Y., Kim, S., Kim, S.J., Yoon, S.H., Cho, K.G., Paek, S.H., Lee, Y.D., Kim, S.S., et al. (2010). The growth of brain tumors can be suppressed by multiple transplantation of mesenchymal stem cells expressing cytosine deaminase. Int. J. Cancer 127, 1975-1983. https://doi.org/10.1002/ijc.25383
  12. Cicalese, M.P., Ferrua, F., Castagnaro, L., Rolfe, K., De Boever, E., Reinhardt, R.R., Appleby, J., Roncarolo, M.G., and Aiuti, A. (2018). Gene therapy for adenosine deaminase deficiency: a comprehensive evaluation of shortand medium-term safety. Mol. Ther. 26, 917-931. https://doi.org/10.1016/j.ymthe.2017.12.022
  13. De Ravin, S.S., Wu, X., Moir, S., Anaya-O'Brien, S., Kwatemaa, N., Littel, P., Theobald, N., Choi, U., Su, L., Marquesen, M., et al. (2016). Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci. Transl. Med. 8, 335ra357.
  14. Dilger, N., Neehus, A.L., Grieger, K., Hoffmann, A., Menssen, M., and Ngezahayo, A. (2020). Gap junction dependent cell communication is modulated during transdifferentiation of mesenchymal stem/stromal cells towards neuron-like cells. Front. Cell Dev. Biol. 8, 869. https://doi.org/10.3389/fcell.2020.00869
  15. Dos Santos, J.F., Borcari, N.R., da Silva Araujo, M., and Nunes, V.A. (2019). Mesenchymal stem cells differentiate into keratinocytes and express epidermal kallikreins: towards an in vitro model of human epidermis. J. Cell. Biochem. 120, 13141-13155. https://doi.org/10.1002/jcb.28589
  16. Field, A.K., Davies, M.E., DeWitt, C., Perry, H.C., Liou, R., Germershausen, J., Karkas, J.D., Ashton, W.T., Johnston, D.B., and Tolman, R.L. (1983). 9-([2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine: a selective inhibitor of herpes group virus replication. Proc. Natl. Acad. Sci. U. S. A. 80, 4139-4143. https://doi.org/10.1073/pnas.80.13.4139
  17. Fitzgerald, J.C., Weiss, S.L., Maude, S.L., Barrett, D.M., Lacey, S.F., Melenhorst, J.J., Shaw, P., Berg, R.A., June, C.H., Porter, D.L., et al. (2017). Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit. Care Med. 45, e124-e131.
  18. Greco, R., Oliveira, G., Stanghellini, M.T., Vago, L., Bondanza, A., Peccatori, J., Cieri, N., Marktel, S., Mastaglio, S., Bordignon, C., et al. (2015). Improving the safety of cell therapy with the TK-suicide gene. Front. Pharmacol. 6, 95. https://doi.org/10.3389/fphar.2015.00095
  19. Hacein-Bey-Abina, S., Le Deist, F., Carlier, F., Bouneaud, C., Hue, C., De Villartay, J.P., Thrasher, A.J., Wulffraat, N., Sorensen, R., Dupuis-Girod, S., et al. (2002). Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N. Engl. J. Med. 346, 1185-1193. https://doi.org/10.1056/NEJMoa012616
  20. Hacein-Bey-Abina, S., Pai, S.Y., Gaspar, H.B., Armant, M., Berry, C.C., Blanche, S., Bleesing, J., Blondeau, J., de Boer, H., Buckland, K.F., et al. (2014). A modified γ-retrovirus vector for X-linked severe combined immunodeficiency. N. Engl. J. Med. 371, 1407-1417. https://doi.org/10.1056/NEJMoa1404588
  21. Hall, S.J., Sanford, M.A., Atkinson, G., and Chen, S.H. (1998). Induction of potent antitumor natural killer cell activity by herpes simplex virus-thymidine kinase and ganciclovir therapy in an orthotopic mouse model of prostate cancer. Cancer Res. 58, 3221-3225.
  22. Hetzel, M., Suzuki, T., Hashtchin, A.R., Arumugam, P., Carey, B., Schwabbauer, M., Kuhn, A., Meyer, J., Schambach, A., Van Der Loo, J., et al. (2017). Function and safety of lentivirus-mediated gene transfer for CSF2RA-deficiency. Hum. Gene Ther. Methods 28, 318-329. https://doi.org/10.1089/hgtb.2017.092
  23. Huang, P., Wang, L., Li, Q., Xu, J., Xu, J., Xiong, Y., Chen, G., Qian, H., Jin, C., Yu, Y., et al. (2019). Combinatorial treatment of acute myocardial infarction using stem cells and their derived exosomes resulted in improved heart performance. Stem Cell Res. Ther. 10, 300. https://doi.org/10.1186/s13287-019-1353-3
  24. Kalos, M., Levine, B.L., Porter, D.L., Katz, S., Grupp, S.A., Bagg, A., and June, C.H. (2011). T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73. https://doi.org/10.1126/scitranslmed.3002842
  25. Kan, I., Ben-Zur, T., Barhum, Y., Levy, Y.S., Burstein, A., Charlow, T., Bulvik, S., Melamed, E., and Offen, D. (2007). Dopaminergic differentiation of human mesenchymal stem cells--utilization of bioassay for tyrosine hydroxylase expression. Neurosci. Lett. 419, 28-33. https://doi.org/10.1016/j.neulet.2007.03.070
  26. Kim, S.S., Choi, J.M., Kim, J.W., Ham, D.S., Ghil, S.H., Kim, M.K., Kim-Kwon, Y., Hong, S.Y., Ahn, S.C., Kim, S.U., et al. (2005). cAMP induces neuronal differentiation of mesenchymal stem cells via activation of extracellular signal-regulated kinase/MAPK. Neuroreport 16, 1357-1361. https://doi.org/10.1097/01.wnr.0000175243.12966.f5
  27. Kim, S.S., Kim, B.J., and Suh-Kim, H. (2003). The efficient gene delivery into human mesenchymal stem cells using retroviral vectors. Korean J. Anat. 36, 381-387.
  28. Kim, S.S., Yoo, S.W., Park, T.S., Ahn, S.C., Jeong, H.S., Kim, J.W., Chang, D.Y., Cho, K.G., Kim, S.U., Huh, Y., et al. (2008). Neural induction with neurogenin1 increases the therapeutic effects of mesenchymal stem cells in the ischemic brain. Stem Cells 26, 2217-2228. https://doi.org/10.1634/stemcells.2008-0108
  29. Le Blanc, K., Rasmusson, I., Sundberg, B., Gotherstrom, C., Hassan, M., Uzunel, M., and Ringden, O. (2004). Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363, 1439-1441. https://doi.org/10.1016/S0140-6736(04)16104-7
  30. Le Blanc, K., Tammik, C., Rosendahl, K., Zetterberg, E., and Ringden, O. (2003). HLA expression and immunologic propertiesof differentiated and undifferentiated mesenchymal stem cells. Exp. Hematol. 31, 890-896. https://doi.org/10.1016/S0301-472X(03)00110-3
  31. Lee, S.H., Jin, K.S., Bang, O.Y., Kim, B.J., Park, S.J., Lee, N.H., Yoo, K.H., Koo, H.H., and Sung, K.W. (2015). Differential migration of mesenchymal stem cells to ischemic regions after middle cerebral artery occlusion in rats. PLoS One 10, e0134920. https://doi.org/10.1371/journal.pone.0134920
  32. Lee, T.Y., Cho, I.S., Bashyal, N., Naya, F.J., Tsai, M.J., Yoon, J.S., Choi, J.M., Park, C.H., Kim, S.S., and Suh-Kim, H. (2020). ERK regulates NeuroD1-mediated neurite outgrowth via proteasomal degradation. Exp. Neurobiol. 29, 189-206. https://doi.org/10.5607/en20021
  33. Lin, P., Lin, Y., Lennon, D.P., Correa, D., Schluchter, M., and Caplan, A.I. (2012). Efficient lentiviral transduction of human mesenchymal stem cells that preserves proliferation and differentiation capabilities. Stem Cells Transl. Med. 1, 886-897. https://doi.org/10.5966/sctm.2012-0086
  34. Locke, F.L., Ghobadi, A., Jacobson, C.A., Miklos, D.B., Lekakis, L.J., Oluwole, O.O., Lin, Y., Braunschweig, I., Hill, B.T., Timmerman, J.M., et al. (2019). Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 20, 31-42. https://doi.org/10.1016/S1470-2045(18)30864-7
  35. Ma, T., Gong, K., Ao, Q., Yan, Y., Song, B., Huang, H., Zhang, X., and Gong, Y. (2013). Intracerebral transplantation of adipose-derived mesenchymal stem cells alternatively activates microglia and ameliorates neuropathological deficits in Alzheimer's disease mice. Cell Transplant. 22 Suppl 1, S113-S126.
  36. Marasini, S., Chang, D.Y., Jung, J.H., Lee, S.J., Cha, H.L., Suh-Kim, H., and Kim, S.S. (2017). Effects of adenoviral gene transduction on the stemness of human bone marrow mesenchymal stem cells. Mol. Cells 40, 598-605. https://doi.org/10.14348/molcells.2017.0095
  37. Marsden, H.S., Haarr, L., and Preston, C.M. (1983). Processing of herpes simplex virus proteins and evidence that translation of thymidine kinase mRNA is initiated at three separate AUG codons. J. Virol. 46, 434-445. https://doi.org/10.1128/jvi.46.2.434-445.1983
  38. Mazzini, L., Fagioli, F., Boccaletti, R., Mareschi, K., Oliveri, G., Olivieri, C., Pastore, I., Marasso, R., and Madon, E. (2003). Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 4, 158-161. https://doi.org/10.1080/14660820310014653
  39. McGarrity, G.J., Hoyah, G., Winemiller, A., Andre, K., Stein, D., Blick, G., Greenberg, R.N., Kinder, C., Zolopa, A., Binder-Scholl, G., et al. (2013). Patient monitoring and follow-up in lentiviral clinical trials. J. Gene Med. 15, 78-82. https://doi.org/10.1002/jgm.2691
  40. Mesnil, M. and Yamasaki, H. (2000). Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: role of gapjunctional intercellular communication. Cancer Res. 60, 3989-3999.
  41. Naldini, L. (2011). Ex vivo gene transfer and correction for cell-based therapies. Nat. Rev. Genet. 12, 301-315. https://doi.org/10.1038/nrg2985
  42. Neelapu, S.S., Locke, F.L., Bartlett, N.L., Lekakis, L.J., Miklos, D.B., Jacobson, C.A., Braunschweig, I., Oluwole, O.O., Siddiqi, T., Lin, Y., et al. (2017). Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531-2544. https://doi.org/10.1056/nejmoa1707447
  43. Park, J.S., Chang, D.Y., Kim, J.H., Jung, J.H., Park, J., Kim, S.H., Lee, Y.D., Kim, S.S., and Suh-Kim, H. (2013). Retrovirus-mediated transduction of a cytosine deaminase gene preserves the stemness of mesenchymal stem cells. Exp. Mol. Med. 45, e10. https://doi.org/10.1038/emm.2013.21
  44. Park, J.S., Suryaprakash, S., Lao, Y.H., and Leong, K.W. (2015). Engineering mesenchymal stem cells for regenerative medicine and drug delivery. Methods 84, 3-16. https://doi.org/10.1016/j.ymeth.2015.03.002
  45. Pittenger, M.F., Mackay, A.M., Beck, S.C., Jaiswal, R.K., Douglas, R., Mosca, J.D., Moorman, M.A., Simonetti, D.W., Craig, S., and Marshak, D.R. (1999). Multilineage potential of adult human mesenchymal stem cells. Science 284, 143-147. https://doi.org/10.1126/science.284.5411.143
  46. Poudineh, M., Wang, Z., Labib, M., Ahmadi, M., Zhang, L., Das, J., Ahmed, S., Angers, S., and Kelley, S.O. (2018). Three-dimensional nanostructured architectures enable efficient neural differentiation of mesenchymal stem cells via mechanotransduction. Nano Lett. 18, 7188-7193. https://doi.org/10.1021/acs.nanolett.8b03313
  47. Preuss, E., Treschow, A., Newrzela, S., Brucher, D., Weber, K., Felldin, U., Alici, E., Gahrton, G., von Laer, D., Dilber, M.S., et al. (2010). TK.007: a novel, codon-optimized HSVtk(A168H) mutant for suicide gene therapy. Hum. Gene Ther. 21, 929-941. https://doi.org/10.1089/hum.2009.042
  48. Ramos, C.A., Asgari, Z., Liu, E., Yvon, E., Heslop, H.E., Rooney, C.M., Brenner, M.K., and Dotti, G. (2010). An inducible caspase 9 suicide gene to improve the safety of mesenchymal stromal cell therapies. Stem Cells 28, 1107-1115. https://doi.org/10.1002/stem.433
  49. Reardon, J.E. (1989). Herpes simplex virus type 1 and human DNA polymerase interactions with 2'-deoxyguanosine 5'-triphosphate analogues. Kinetics of incorporation into DNA and induction of inhibition. J. Biol. Chem. 264, 19039-19044. https://doi.org/10.1016/S0021-9258(19)47263-3
  50. Rothenburger, T., Thomas, D., Schreiber, Y., Wratil, P.R., Pflantz, T., Knecht, K., Digianantonio, K., Temple, J., Schneider, C., Baldauf, H.M., et al. (2021). Differences between intrinsic and acquired nucleoside analogue resistance in acute myeloid leukaemia cells. J. Exp. Clin. Cancer Res. 40, 317. https://doi.org/10.1186/s13046-021-02093-4
  51. Schuster, S.J., Bishop, M.R., Tam, C.S., Waller, E.K., Borchmann, P., McGuirk, J.P., Jager, U., Jaglowski, S., Andreadis, C., Westin, J.R., et al. (2019). Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 380, 45-56. https://doi.org/10.1056/NEJMoa1804980
  52. Sgodda, M., Aurich, H., Kleist, S., Aurich, I., Konig, S., Dollinger, M.M., Fleig, W.E., and Christ, B. (2007). Hepatocyte differentiation of mesenchymal stem cells from rat peritoneal adipose tissue in vitro and in vivo. Exp. Cell Res. 313, 2875-2886. https://doi.org/10.1016/j.yexcr.2007.05.020
  53. Shin, J.W., Ryu, S., Ham, J., Jung, K., Lee, S., Chung, D.H., Kang, H.R., and Kim, H.Y. (2021). Mesenchymal stem cells suppress severe asthma by directly regulating Th2 cells and type 2 innate lymphoid cells. Mol. Cells 44, 580-590. https://doi.org/10.14348/molcells.2021.0101
  54. Suzuki, M., McHugh, J., Tork, C., Shelley, B., Hayes, A., Bellantuono, I., Aebischer, P., and Svendsen, C.N. (2008). Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS. Mol. Ther. 16, 2002-2010. https://doi.org/10.1038/mt.2008.197
  55. Szaraz, P., Gratch, Y.S., Iqbal, F., and Librach, C.L. (2017). In vitro differentiation of human mesenchymal stem cells into functional cardiomyocyte-like cells. J. Vis. Exp. (126), 55757.
  56. Tani, K. (2016). Current status of ex vivo gene therapy for hematological disorders: a review of clinical trials in Japan around the world. Int. J. Hematol. 104, 42-72. https://doi.org/10.1007/s12185-016-2030-2
  57. Tomayko, M.M. and Reynolds, C.P. (1989). Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother. Pharmacol. 24, 148-154. https://doi.org/10.1007/BF00300234
  58. Unsal, I.O., Ginis, Z., Pinarli, F.A., Albayrak, A., Cakal, E., Sahin, M., and Delibasi, T. (2015). Comparison of therapeutic characteristics of islet cell transplantation simultaneous with pancreatic mesenchymal stem cell transplantation in rats with Type 1 diabetes mellitus. Stem Cell Rev. Rep. 11, 526-532. https://doi.org/10.1007/s12015-014-9563-7
  59. Valiunas, V., Doronin, S., Valiuniene, L., Potapova, I., Zuckerman, J., Walcott, B., Robinson, R.B., Rosen, M.R., Brink, P.R., and Cohen, I.S. (2004). Human mesenchymal stem cells make cardiac connexins and form functional gap junctions. J. Physiol. 555, 617-626. https://doi.org/10.1113/jphysiol.2003.058719
  60. van Dillen, I.J., Mulder, N.H., Vaalburg, W., de Vries, E.F., and Hospers, G.A. (2002). Influence of the bystander effect on HSV-tk/GCV gene therapy. A review. Curr. Gene Ther. 2, 307-322. https://doi.org/10.2174/1566523023347733
  61. Wang, F., Yasuhara, T., Shingo, T., Kameda, M., Tajiri, N., Yuan, W.J., Kondo, A., Kadota, T., Baba, T., Tayra, J.T., et al. (2010). Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: focusing on neuroprotective effects of stromal cell-derived factor-1alpha. BMC Neurosci. 11, 52. https://doi.org/10.1186/1471-2202-11-52
  62. Wang, M., Munoz, J., Goy, A., Locke, F.L., Jacobson, C.A., Hill, B.T., Timmerman, J.M., Holmes, H., Jaglowski, S., Flinn, I.W., et al. (2020). KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 382, 1331-1342. https://doi.org/10.1056/nejmoa1914347
  63. Xin, H., Li, Y., Cui, Y., Yang, J.J., Zhang, Z.G., and Chopp, M. (2013). Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J. Cereb. Blood Flow Metab. 33, 1711-1715. https://doi.org/10.1038/jcbfm.2013.152
  64. Yang, H., Yang, H., Xie, Z., Wei, L., and Bi, J. (2013). Systemic transplantation of human umbilical cord derived mesenchymal stem cells-educated T regulatory cells improved the impaired cognition in AβPPswe/PS1dE9 transgenic mice. PLoS One 8, e69129. https://doi.org/10.1371/journal.pone.0069129
  65. Zhang, X., Chen, J., Liu, A., Xu, X., Xue, M., Xu, J., Yang, Y., Qiu, H., and Guo, F. (2018). Stable overexpression of p130/E2F4 affects the multipotential abilities of bone-marrow-derived mesenchymal stem cells. J. Cell. Physiol. 233, 9739-9749. https://doi.org/10.1002/jcp.26926
  66. Zhang, Y., Huang, X., and Yuan, Y. (2017). MicroRNA-410 promotes chondrogenic differentiation of human bone marrow mesenchymal stem cells through down-regulating Wnt3a. Am. J. Transl. Res. 9, 136-145.
  67. Zhang, Z., Lin, J., Chu, J., Ma, Y., Zeng, S., and Luo, Q. (2008). Activation of caspase-3 noninvolved in the bystander effect of the herpes simplex virus thymidine kinase gene/ganciclovir (HSV-tk/GCV) system. J. Biomed. Opt. 13, 031209. https://doi.org/10.1117/1.2937830