Progress of mesenchymal stem cells by spheroid culture

doi:10.3877/cma.j.issn.2095-1221.2021.06.008

Abstract

Abstract:

Mesenchymal stem cells (MSCs) play an important role in tissue engineering and regenerative medicine applications for their self-renewal ability and multidirectional differentiation potential. However, there are many difficulties in the clinical application of MSCs, such as the low survival rate after in vivo transplantation, and the attenuation of MSCs characteristics in the traditional culture. Spheroid culture is a scaffold-free-mediated three-dimensional (3D) culture system. Multiple types of cells have the advantage of natural self aggregation tendency, which can provide a preferable physiological microenvironment for cells growth in vivo. Scholars have made related researches and progress. Studies have shown that spheroid culture can maintain properties of MSCs and explore its therapeutic potential in clinical applications. Therefore, spheroid culture is promising in medicine applications, and in this paper the progress of MSCs by spheroid culture will be reviewed.

Key words: Mesenchymal stem cells, Spheroid, Microenvironment, Stemness, Therapeutic potential

Tingting Liang, Shichang Zhang. Progress of mesenchymal stem cells by spheroid culture[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2021, 11(06): 372-377.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhxbygxbzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.2095-1221.2021.06.008

https://zhxbygxbzz.cma-cmc.com.cn/EN/Y2021/V11/I06/372

Figures/Tables 2

References 45

1	Liu Q, Huang Q, Wu H, et al. Characteristics and therapeutic potential of human amnion-derived stem cells[J]. Int J Mol Sci, 2021, 22(2):970.
2	Teixeira F, Carvalho M, Sousa N, et al. Mesenchymal stem cells secretome: a new paradigm for central nervous system regeneration?[J]. Cell Mol Life Sci, 2013, 70(20):3871-3882.
3	Li F, Truong V, Thissen H, et al. Microfluidic encapsulation of human mesenchymal stem cells for articular cartilage tissue regeneration[J]. ACS Appl Mater Interfaces, 2017, 9(10):8589-8601.
4	Turinetto V, Vitale E, Giachino C. Senescence in human mesenchymal stem cells: functional changes and implications in stem cell-based therapy[J]. Int J Mol Sci, 2016, 17(7):1164.
5	Yan X, van den Beucken J, Both S, et al. Biomaterial strategies for stem cell maintenance during in vitro expansion[J]. Tissue Eng Part B Rev, 2014, 20(4):340-354.
6	Panek M, Grabacka M, Pierzchalska M. The formation of intestinal organoids in a hanging drop culture[J]. Cytotechnology, 2018, 70(3): 1085-1095.
7	Bartosh T, Ylostalo J. Preparation of anti-inflammatory mesenchymal stem/precursor cells (MSCs) through sphere formation using hanging-drop culture technique[J]. Curr Protoc Stem Cell Biol, 2014, 28:Unit 2B.6.doi: 10.1002/9780470151808.sc02b06s28.
8	Bartosh T, Ylöstalo J, Mohammadipoor A, et al. Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties[J]. Proc Natl Acad Sci U S A, 2010, 107(31):13724-13729.
9	Costăchel O, Fadei L, Badea E. Tumor cell suspension culture on non adhesive substratum[J]. Z Krebsforsch, 1969, 72(1):24-31.
10	Sackmann E, Smith A. Physics of cell adhesion: some lessons from cell-mimetic systems[J]. Soft matter, 2014, 10(11):1644-1659.
11	Carvalho M, Costa E, Correia I. Assembly of breast cancer heterotypic spheroids on hyaluronic acid coated surfaces[J]. Biotechnol Prog, 2017, 33(5):1346-1357.
12	Iwashita M, Ohta H, Fujisawa T, et al. Brain-stiffness-mimicking tilapia collagen gel promotes the induction of dorsal cortical neurons from human pluripotent stem cells[J]. Sci Rep, 2019, 9(1):3068.
13	Kim S, Kim E, Yamamoto M, et al. Engineering multi-cellular spheroids for tissue engineering and regenerative medicine[J]. Adv Healthc Mater, 2020:e2000608. doi: 10.1002/adhm.202000608.
14	Zhao N, Coyne J, Abune L, et al. Exogenous signaling molecules released from aptamer-functionalized hydrogels promote the survival of mesenchymal stem cell spheroids[J]. ACS Appl Mater Interfaces, 2020, 12(22):24599-24610.
15	Kim G, Jung Y, Cho K, et al. Thermoresponsive poly (N-isopropylacrylamide) hydrogel substrates micropatterned with poly (ethylene glycol) hydrogel for adipose mesenchymal stem cell spheroid formation and retrieval[J]. Mater Sci Eng C Mater Biol Appl, 2020, 115: 111128.
16	Li Y, Kumacheva E. Hydrogel microenvironments for cancer spheroid growth and drug screening[J]. Sci Adv, 2018, 4(4):eaas8998.doi: 10.1126/sciadv.aas8998.
17	Mattix B, Olsen T, Gu Y, et al. Biological magnetic cellular spheroids as building blocks for tissue engineering[J]. Acta Biomater, 2014, 10(2):623-629.
18	Labusca L, Herea D, Radu E, et al. Human adipose derived stem cells and osteoblasts interaction with Fe-Cr-Nb-B magnetic nanoparticles[J]. J Nanosci Nanotechnol, 2018, 18(7):5143-5153.
19	Lewis N, Lewis E, Mullin M, et al. Magnetically levitated mesenchymal stem cell spheroids cultured with a collagen gel maintain phenotype and quiescence[J]. J Tissue Eng, 2017, 8:2041731417704428. doi: 10.1177/2041731417704428.
20	Achilli T, Meyer J, Morgan J. Advances in the formation, use and understanding of multi-cellular spheroids[J]. Expert Opin Biol Ther, 2012, 12(10):1347-1360.
21	Zhang S, Zhang B, Chen X, et al. Three-dimensional culture in a microgravity bioreactor improves the engraftment efficiency of hepatic tissue constructs in mice[J]. J Mater Sci Mater Med, 2014, 25(12):2699-2709.
22	Si A, Wang L, Miao K, et al. miR-219 regulates liver cancer stem cell expansion via E-cadherin pathway[J]. Cell cycle, 2019, 18(24):3550-3561.
23	Lee B, Kim M, Lee J, et al. Modulation of Huh7.5 spheroid formation and functionality using modified PEG-based hydrogels of different stiffness[J]. PLoS One, 2015, 10(2):e0118123. doi: 10.1371/journal.pone.0118123.
24	Tsai A, Liu Y, Yuan X, et al. Compaction, fusion, and functional activation of three-dimensional human mesenchymal stem cell aggregate[J]. Tissue Eng Part A, 2015, 21(9-10):1705-1719.
25	Cui X, Hartanto Y, Zhang H. Advances in multicellular spheroids formation[J]. J R Soc Interface, 2017, 14(127):20160877. doi: 10.1098/rsif.2016.0877.
26	Zhang Y, Mao H, Gao C, et al. Enhanced biological functions of human mesenchymal stem-cell aggregates incorporating E-cadherin-modified plga microparticles[J]. Adv Healthc Mater, 2016, 5(15):1949-1959.
27	Lee E, Park S, Kang S, et al. Spherical bullet formation via E-cadherin promotes therapeutic potency of mesenchymal stem cells derived from human umbilical cord blood for myocardial infarction[J]. Mol Ther, 2012, 20(7):1424-1433.
28	Sen B, Guilluy C, Xie Z, et al. Mechanically induced focal adhesion assembly amplifies anti-adipogenic pathways in mesenchymal stem cells[J]. Stem cells, 2011, 29(11):1829-1836.
29	Zhou Y, Chen H, Li H, et al. 3D culture increases pluripotent gene expression in mesenchymal stem cells through relaxation of cytoskeleton tension[J]. J Cell Mol Med, 2017, 21(6):1073-1084.
30	Cheng N, Chen S, Li J, et al. Short-term spheroid formation enhances the regenerative capacity of adipose-derived stem cells by promoting stemness, angiogenesis, and chemotaxis[J]. Stem Cells Transl Med, 2013, 2(8):584-594.
31	Zhang S, Liu P, Chen L, et al. The effects of spheroid formation of adipose-derived stem cells in a microgravity bioreactor on stemness properties and therapeutic potential[J]. Biomaterials, 2015, 41:15-25.
32	Tsai A, Liu Y, Yuan X, et al. Aggregation kinetics of human mesenchymal stem cells under wave motion[J]. Biotechnol J, 2017, 12(5). doi: 10.1002/biot.201600448.
33	Cheng N, Wang S, Young T. The influence of spheroid formation of human adipose-derived stem cells on chitosan films on stemness and differentiation capabilities[J]. Biomaterials, 2012, 33(6):1748-1758.
34	Yeh H, Liu B, Sieber M, et al. Substrate-dependent gene regulation of self-assembled human MSC spheroids on chitosan membranes[J]. BMC Genomics, 2014, 15(1):10.
35	Miceli V, Pampalone M, Vella S, et al. Comparison of immunosuppressive and angiogenic properties of human amnion-derived mesenchymal stem cells between 2D and 3D culture systems[J]. Stem Cells Int, 2019, 2019:7486279.doi: 10.1155/2019/7486279.
36	Park I, Chung P, Ahn J, et al. Human adipose-derived stem cell spheroid treated with photobiomodulation irradiation accelerates tissue regeneration in mouse model of skin flap ischemia[J]. Lasers Med Sci, 2017, 32(8):1737-1746.
37	Mohammadi Ghahhari N, Maghsood F, Jahandideh S, et al. Secretome of aggregated embryonic stem cell-derived mesenchymal stem cell modulates the release of inflammatory factors in lipopolysaccharide-induced peripheral blood mononuclear cells[J]. Iran Biomed J, 2018, 22(4):237-245.
38	Zimmermann J, McDevitt T. Pre-conditioning mesenchymal stromal cell spheroids for immunomodulatory paracrine factor secretion[J]. Cytotherapy, 2014, 16(3):331-345.
39	Domnina A, Novikova P, Obidina J, et al. Human mesenchymal stem cells in spheroids improve fertility in model animals with damaged endometrium[J]. Stem Cell Res Ther, 2018, 9(1):50.
40	Domnina A, Ivanova J, Alekseenko L, et al. Three-dimensional compaction switches stress response programs and enhances therapeutic efficacy of endometrial mesenchymal stem/stromal cells[J]. Front Cell Dev Biol, 2020, 8:473. doi: 10.3389/fcell.2020.00473.
41	Keung A, Kumar S, Schaffer D. Presentation counts: microenvironmental regulation of stem cells by biophysical and material cues[J]. Annu Rev Cell Dev Biol, 2010, 26:533-556.
42	Schmitz C, Pepelanova I, Seliktar D, et al. Live reporting for hypoxia: Hypoxia sensor-modified mesenchymal stem cells as in vitro reporters[J]. Biotechnol Bioeng, 2020, 117(11):3265-3276.
43	Cesarz Z, Tamama K. Spheroid Culture of Mesenchymal Stem Cells[J]. Stem Cells Int, 2016, 2016:9176357. doi: 10.1155/2016/9176357.
44	Jiang Z, Li Y, Ji X, et al. Protein profiling identified key chemokines that regulate the maintenance of human pluripotent stem cells[J]. Sci Rep, 2017, 7(1):14510.
45	Guo L, Zhou Y, Wang S, et al. Epigenetic changes of mesenchymal stem cells in three-dimensional (3D) spheroids[J]. J Cell Mol Med, 2014, 18(10):2009-2019.

方法	原理	优点	缺点
悬滴培养法	利用表面张力和重力	可调节球体大小	难以实现大规模培养
液体覆盖法	使用非黏性材料抑制细胞附着	适合长期培养	难以控制球体大小
水凝胶法	提供与ECM相似的微环境	维持MSCs干性	影响MSCs的完整性
磁性粒子法	利用磁力促进细胞黏附	加快成球速率	涉及安全性问题
动态培养	动力阻止细胞贴壁	大规模生产	需要特定装置

方法	原理	优点	缺点
悬滴培养法	利用表面张力和重力	可调节球体大小	难以实现大规模培养
液体覆盖法	使用非黏性材料抑制细胞附着	适合长期培养	难以控制球体大小
水凝胶法	提供与ECM相似的微环境	维持MSCs干性	影响MSCs的完整性
磁性粒子法	利用磁力促进细胞黏附	加快成球速率	涉及安全性问题
动态培养	动力阻止细胞贴壁	大规模生产	需要特定装置

[1]	Kang Li, Liang Ji, Wei Zhao, Lemin Lin. Dual role of autophagy in biological progression of breast cancer [J]. Chinese Journal of Breast Disease(Electronic Edition), 2023, 17(04): 195-202.
[2]	Yangwenxiang Wei, Haoran Huang, Yuhao Liu, Zhenqiu Chen, Haibin Wang, Chi Zhou. Outlooks and challenges in cell therapy of osteonecrosis of femoral head [J]. Chinese Journal of Joint Surgery(Electronic Edition), 2023, 17(05): 694-700.
[3]	Zhuoyi Fu, Shengcheng Tang, Qiaomei Bu, Gaobing Xu, Anping Wu, Wei Cai, Ming Yang, Haitao Tan. Research progress of magnesium in treatment of osteoarthritis [J]. Chinese Journal of Joint Surgery(Electronic Edition), 2023, 17(03): 354-362.
[4]	Chenxi Li, Xiaorong Tan, Wei Wei, Muqiu Li, Zhongcheng Gong. Characteristics and significance of tertiary lymphoid structures in oral cancer [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2023, 17(05): 315-321.
[5]	Changqing Cao, Xinyan Guo, Yuan Gao, Cun Zhang, Haili Tang, Dong Fan, Xiaojun Yang, Song Zhang, Huadong Zhao. Research progress on the involvement of tumor microenvironment in mediating trastuzumab resistance in HER2-positive breast cancer [J]. Chinese Journal of Operative Procedures of General Surgery(Electronic Edition), 2024, 18(01): 90-95.
[6]	Weixuan Pan, Shaolong Hao, Wei Han. Research progress of hypoxic microenvironment and m6A modification in solid malignant tumors [J]. Chinese Journal of Operative Procedures of General Surgery(Electronic Edition), 2023, 17(04): 461-464.
[7]	Yingjun Tang, Huajuan Li, Saini Wang, Wang Xu, Feng Liu, Xi Li, Xinbao Hao, Huaping Huang. Effect and mechanism of human umbilical cord mesenchymal stem cells (HU-MSCs) transplantation on emphysema mice [J]. Chinese Journal of Lung Diseases(Electronic Edition), 2023, 16(04): 476-480.
[8]	Ye Li, Jie He, Jinxiu Hu, Jinxiang Wang, Chuan Tian, Hang Pan, Mengdie Chen, Xiaojuan Zhao, Li Ye, Min Zhang, Xinghua Pan. Highly active mesenchymal stem cells interfere with ovarian aging in macaques [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(04): 210-219.
[9]	Huiling Long, Mi Lin, Ting Shao. Research progress and application of three-dimensional spherical mesenchymal stem cell culture technology [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(04): 229-234.
[10]	Wenhui Liu, Tao Wu, Xi Zhang. Advances in mesenchymal stem cells combined with thrombopoietin receptor agonists in platelet recovery after allogeneic hematopoietic stem cell transplantation [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(04): 242-246.
[11]	Hongmin Wang, Yunbo Xie, Yanhu Wang, Fusheng Wang. The advance of clinical research in mesenchymal stem cell treatment for COVID-19 [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(04): 247-256.
[12]	Fuhao Qin, Zheng Zheng, Bin Jiang. Research progress of mesenchymal stem cells in the treatment of perianal fifistulizing Crohn's disease [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(03): 172-177.
[13]	Yanqi Song, Xuejing Ren, Wenjuan Wang, Qiuxia Han, Yue Xu, Kaiting Zhuang, Tuo Xiao, Guangyan Cai. Effect of mesenchymal stem cells on ferroptosis in cisplatin-induced acute kidney injury of mice [J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2023, 12(04): 187-193.
[14]	Yunzhao Yang, Cheng Zhou, Meihan Shi, Jing Zhao, Xueyuan Bai. Therapeutic effect of human amniotic fluid-derived mesenchymal stem cells on membranous nephropathy in rats [J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2023, 12(04): 181-186.
[15]	Xiuyan Sun, Qinglei Xu, Pengtao Ma, Zhiyuan Hu, Chuanzhen Guo, Chenghong Zhu. Correlation analysis of body temperature changes during laparoscopic radical gastrectomy with pressure injury and microenvironment of the compression site [J]. Chinese Journal of Digestion and Medical Imageology(Electronic Edition), 2023, 13(06): 480-484.

Please choose a citation manager

Content to export