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With the increasing understanding of mesenchymal stem cells (MSCs), their potential in tissue engineering and regenerative medicine has attracted more attention. However, some important problems need to be solved before clinical application, such as low amplification efficiency, inconsistent cell product quality, and unsatisfactory survival rate at the receptor site. Telomeres act as a clock, and they shorten when cells divide. The main mechanism for reversing telomere length is telomerase. Furthermore, telomerase is involved in antioxidation, antiapoptosis, immunological modulation, and other noncanonical processes in addition to proliferation-related tasks. Therefore, it is necessary to understand the telomere biology and telomerase of MSCs to improve their proliferation, performance stability, and antiscavenging ability. This review summarizes the progress of telomerase biological function and mechanism in MSCs, and discusses the current situation and deficiency of telomerase-related application in MSCs.

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Application of telomere biology and telomerase in mesenchymal stem cells

Show Author's information Shuili Jing1,§Heng Zhou1,§Chen Zou2,§David P. C. Chen3Qingsong Ye1( )Yilong Ai2( )Yan He4( )
Center of Regenerative Medicine & Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
Foshan Hospital of Stomatology, School of Medicine, Foshan University, Foshan 528225, China
School of Dentistry, University of Queensland, Herston, QLD 4006, Australia
Institute of Regenerative and Translational Medicine, Tianyou Hospital of Wuhan University of Science and Technology, Wuhan 430064, China

§ Shuili Jing, Heng Zhou, and Chen Zou contributed equally to this work.


With the increasing understanding of mesenchymal stem cells (MSCs), their potential in tissue engineering and regenerative medicine has attracted more attention. However, some important problems need to be solved before clinical application, such as low amplification efficiency, inconsistent cell product quality, and unsatisfactory survival rate at the receptor site. Telomeres act as a clock, and they shorten when cells divide. The main mechanism for reversing telomere length is telomerase. Furthermore, telomerase is involved in antioxidation, antiapoptosis, immunological modulation, and other noncanonical processes in addition to proliferation-related tasks. Therefore, it is necessary to understand the telomere biology and telomerase of MSCs to improve their proliferation, performance stability, and antiscavenging ability. This review summarizes the progress of telomerase biological function and mechanism in MSCs, and discusses the current situation and deficiency of telomerase-related application in MSCs.

Keywords: nanoprobe, mesenchymal stem cells (MSCs), senescence, telomere biology, telomerase



Friedenstein, A. J.; Chailakhyan, R. K.; Latsinik, N. V.; Panasyuk, A. F.; Keiliss-Borok, I. V. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 1974, 14, 331–340.


Smith, E. M.; Pendlebury, D. F.; Nandakumar, J. Structural biology of telomeres and telomerase. Cell. Mol. Life Sci. 2020, 77, 61–79.


Rosen, J.; Jakobs, P.; Ale-Agha, N.; Altschmied, J.; Haendeler, J. Non-canonical functions of telomerase reverse transcriptase-impact on redox homeostasis. Redox Biol. 2020, 34, 101543.


Greider, C. W. Telomeres do D-loop-T-loop. Cell 1999, 97, 419–422.


Roake, C. M.; Artandi, S. E. Regulation of human telomerase in homeostasis and disease. Nat. Rev. Mol. Cell Biol. 2020, 21, 384–397.


Palm, W.; de Lange, T. How shelterin protects mammalian telomeres. Annu. Rev. Genet. 2008, 42, 301–334.


He, Y.; Wang, Y. Q.; Liu, B. C.; Helmling, C.; Sušac, L.; Cheng, R.; Zhou, Z. H.; Feigon, J. Structures of telomerase at several steps of telomere repeat synthesis. Nature 2021, 593, 454–459.


Ghanim, G. E.; Fountain, A. J.; van Roon, A. M. M.; Rangan, R.; Das, R.; Collins, K.; Nguyen, T. H. D. Structure of human telomerase holoenzyme with bound telomeric DNA. Nature 2021, 593, 449–453.


Srinivas, N.; Rachakonda, S.; Kumar, R. Telomeres and telomere length: A general overview. Cancers (Basel) 2020, 12, 558.


Calado, R. T.; Dumitriu, B. Telomere dynamics in mice and humans. Semin. Hematol. 2013, 50, 165–174.


Whittemore, K.; Vera, E.; Martínez-Nevado, E.; Sanpera, C.; Blasco, M. A. Telomere shortening rate predicts species life span. Proc. Natl. Acad. Sci. USA 2019, 116, 15122–15127.


Shay, J. W.; Wright, W. E. Telomeres and telomerase in normal and cancer stem cells. FEBS Lett. 2010, 584, 3819–3825.


Prowse, K. R.; Greider, C. W. Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc. Natl. Acad. Sci. USA 1995, 92, 4818–4822.


Gomes, N. M. V.; Ryder, O. A.; Houck, M. L.; Charter, S. J.; Walker, W.; Forsyth, N. R.; Austad, S. N.; Venditti, C.; Pagel, M.; Shay, J. W. et al. Comparative biology of mammalian telomeres: Hypotheses on ancestral states and the roles of telomeres in longevity determination. Aging Cell 2011, 10, 761–768.


van Deursen, J. M. The role of senescent cells in ageing. Nature 2014, 509, 439–446.


Di Micco, R.; Krizhanovsky, V.; Baker, D.; d'Adda di Fagagna, F. Cellular senescence in ageing: From mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 2021, 22, 75–95.


Opresko, P. L.; Shay, J. W. Telomere-associated aging disorders. Ageing Res. Rev. 2017, 33, 52–66.


Hayflick, L.; Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 1961, 25, 585–621.


Pańczyszyn, A.; Boniewska-Bernacka, E.; Goc, A. The role of telomeres and telomerase in the senescence of postmitotic cells. DNA Repair (Amst) 2020, 95, 102956.


Barnes, R. P.; Fouquerel, E.; Opresko, P. L. The impact of oxidative DNA damage and stress on telomere homeostasis. Mech. Ageing Dev. 2019, 177, 37–45.


Jeoung, J. Y.; Nam, H. Y.; Kwak, J.; Jin, H. J.; Lee, H. J.; Lee, B. W.; Baek, J. H.; Eom, J. S.; Chang, E. J.; Shin, D. M. et al. A decline in Wnt3a signaling is necessary for mesenchymal stem cells to proceed to replicative senescence. Stem Cells Dev. 2015, 24, 973–982.


Li, Y.; Wu, Q.; Wang, Y. J.; Li, L.; Bu, H.; Bao, J. Senescence of mesenchymal stem cells (Review). Int. J. Mol. Med. 2017, 39, 775–782.


Yang, Y. H. K.; Ogando, C. R.; See, C. W.; Chang, T. Y.; Barabino, G. A. Changes in phenotype and differentiation potential of human mesenchymal stem cells aging in vitro. Stem Cell Res. Ther. 2018, 9, 131.


Sui, B. D.; Hu, C. H.; Zheng, C. X.; Jin, Y. Microenvironmental views on mesenchymal stem cell differentiation in aging. J. Dent. Res. 2016, 95, 1333–1340.


Ahmadi, M.; Rezaie, J. Ageing and mesenchymal stem cells derived exosomes: Molecular insight and challenges. Cell Biochem. Funct. 2021, 39, 60–66.


Wright, W. E.; Piatyszek, M. A.; Rainey, W. E.; Byrd, W.; Shay, J. W. Telomerase activity in human germline and embryonic tissues and cells. Dev. Genet. 1996, 18, 173–179.


Gruber, H. J.; Semeraro, M. D.; Renner, W.; Herrmann, M. Telomeres and age-related diseases. Biomedicines 2021, 9, 1335.


Zimmermann, S.; Voss, M.; Kaiser, S.; Kapp, U.; Waller, C. F.; Martens, U. M. Lack of telomerase activity in human mesenchymal stem cells. Leukemia 2003, 17, 1146–1149.


Zhao, Y. M.; Li, J. Y.; Lan, J. P.; Lai, X. Y.; Luo, Y.; Sun, J.; Yu, J.; Zhu, Y. Y.; Zeng, F. F.; Zhou, Q. et al. Cell cycle dependent telomere regulation by telomerase in human bone marrow mesenchymal stem cells. Biochem. Biophys. Res. Commun. 2008, 369, 1114–1119.


Serakinci, N.; Graakjaer, J.; Kolvraa, S. Telomere stability and telomerase in mesenchymal stem cells. Biochimie 2008, 90, 33–40.


Izadpanah, R.; Trygg, C.; Patel, B.; Kriedt, C.; Dufour, J.; Gimble, J. M.; Bunnell, B. A. Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. J. Cell. Biochem. 2006, 99, 1285–1297.


Ostan, R.; Monti, D.; Gueresi, P.; Bussolotto, M.; Franceschi, C.; Baggio, G. Gender, aging and longevity in humans: An update of an intriguing/neglected scenario paving the way to a gender-specific medicine. Clin. Sci. (Lond. ) 2016, 130, 1711–1725.


Gardner, M.; Bann, D.; Wiley, L.; Cooper, R.; Hardy, R.; Nitsch, D.; Martin-Ruiz, C.; Shiels, P.; Sayer, A. A.; Barbieri, M. et al. Gender and telomere length: Systematic review and meta-analysis. Exp. Gerontol. 2014, 51, 15–27.


Cha, Y.; Kwon, S. J.; Seol, W.; Park, K. S. Estrogen receptor-alpha mediates the effects of estradiol on telomerase activity in human mesenchymal stem cells. Mol. Cells 2008, 26, 454–458.


Hong, L.; Zhang, G. Q.; Sultana, H.; Yu, Y.; Wei, Z. The effects of 17-β estradiol on enhancing proliferation of human bone marrow mesenchymal stromal cells in vitro. Stem Cells Dev. 2011, 20, 925–931.


Zhang, Y. Y.; Lv, P. J.; Li, Y. L.; Zhang, Y. H.; Cheng, C. F.; Hao, H. B.; Yue, H. Comparison of the biological characteristics of umbilical cord mesenchymal stem cells derived from the human heterosexual twins. Differentiation 2020, 114, 1–12.


Bernardo, M. E.; Zaffaroni, N.; Novara, F.; Cometa, A. M.; Avanzini, M. A.; Moretta, A.; Montagna, D.; Maccario, R.; Villa, R.; Daidone, M. G. et al. Human bone marrow-derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res. 2007, 67, 9142–9149.


Nava, M. B.; Catanuto, G.; Pennati, A. E.; Rocco, N.; Spano, A.; Villa, R.; Daidone, M. Lack of activation of telomere maintenance mechanisms in human adipose stromal cells derived from fatty portion of lipoaspirates. Plast. Reconstr. Surg. 2015, 135, 114e–123e.


Colosimo, A.; Russo, V.; Mauro, A.; Curini, V.; Marchisio, M.; Bernabò, N.; Alfonsi, M.; Mattioli, M.; Barboni, B. Prolonged in vitro expansion partially affects phenotypic features and osteogenic potential of ovine amniotic fluid-derived mesenchymal stromal cells. Cytotherapy 2013, 15, 930–950.


Fu, W. L.; Chen, G.; Li, Q.; Tang, X.; Zhang, C. H. Mesenchymal stem cells derived from peripheral blood retain their pluripotency, but undergo senescence during long-term culture. Tissue Eng. Part C: Methods 2015, 21, 1088–1097.


Asumda, F. Z. Age-associated changes in the ecological niche: Implications for mesenchymal stem cell aging. Stem Cell Res. Ther. 2013, 4, 47.


Wu, S. H.; Yu, J. H.; Liao, Y. T.; Liu, K. H.; Chiang, E. R.; Chang, M. C.; Wang, J. P. Comparison of the infant and adult adipose-derived mesenchymal stem cells in proliferation, senescence, anti-oxidative ability and differentiation potential. Tissue Eng. Regen. Med. 2022, 19, 589–601.


Liu, X.Y.; Yin, M. J.; Liu, X. P.; Da, J. L.; Zhang, K.; Zhang, X. J.; Liu, L. X.; Wang, J. Q.; Jin, H.; Liu, Z. S. et al. Analysis of hub genes involved in distinction between aged and fetal bone marrow mesenchymal stem cells by robust rank aggregation and multiple functional annotation methods. Front. Genet. 2020, 11, 573877.


Ock, S. A.; Maeng, G. H.; Lee, Y. M.; Kim, T. H.; Kumar, B. M.; Lee, S. L.; Rho, G. J. Donor-matched functional and molecular characterization of canine mesenchymal stem cells derived from different origins. Cell Transplant. 2013, 22, 2311–2321.


Trivanović, D.; Jauković, A.; Popović, B.; Krstić, J.; Mojsilović, S.; Okić-Djordjević, I.; Kukolj, T.; Obradović, H.; Santibanez, J. F.; Bugarski, D. Mesenchymal stem cells of different origin: Comparative evaluation of proliferative capacity, telomere length and pluripotency marker expression. Life Sci. 2015, 141, 61–73.


Ferreira, M. S. V.; Bienert, M.; Müller, K.; Rath, B.; Goecke, T.; Opländer, C.; Braunschweig, T.; Mela, P.; Brümmendorf, T. H.; Beier, F. et al. Comprehensive characterization of chorionic villi-derived mesenchymal stromal cells from human placenta. Stem Cell Res. Ther. 2018, 9, 28.


Jeon, B. G.; Kang, E. J.; Kumar, B. M.; Maeng, G. H.; Ock, S. A.; Kwack, D. O.; Park, B. W.; Rho, G. J. Comparative analysis of telomere length, telomerase and reverse transcriptase activity in human dental stem cells. Cell Transplant. 2011, 20, 1693–1705.


Santivasi, W. L.; Xia, F. Ionizing radiation-induced DNA damage, response, and repair. Antioxid. Redox Signal. 2014, 21, 251–259.


Orun, O.; Tiber, P. M.; Serakinci, N. Partial knockdown of TRF2 increase radiosensitivity of human mesenchymal stem cells. Int. J. Biol. Macromol. 2016, 90, 53–58.


Sishc, B. J.; Nelson, C. B.; McKenna, M. J.; Battaglia, C. L. R.; Herndon, A.; Idate, R.; Liber, H. L.; Bailey, S. M. Telomeres and telomerase in the radiation response: Implications for instability, reprograming, and carcinogenesis. Front. Oncol. 2015, 5, 257.


Serakinci, N.; Tiber, P. M.; Orun, O. Chromatin modifications of hTERT gene in hTERT-immortalized human mesenchymal stem cells upon exposure to radiation. Eur. J. Med. Genet. 2018, 61, 288–293.


Christensen, R.; Alsner, J.; Sorensen, F. B.; Dagnaes-Hansen, F.; Kolvraa, S.; Serakinci, N. Transformation of human mesenchymal stem cells in radiation carcinogenesis: Long-term effect of ionizing radiation. Regen. Med. 2008, 3, 849–861.


Buttiglieri, S.; Ruella, M.; Risso, A.; Spatola, T.; Silengo, L.; Avvedimento, E. V.; Tarella, C. The aging effect of chemotherapy on cultured human mesenchymal stem cells. Exp. Hematol. 2011, 39, 1171–1181.


Tsai, C. C.; Chen, C. L.; Liu, H. C.; Lee, Y. T.; Wang, H. W.; Hou, L. T.; Hung, S. C. Overexpression of hTERT increases stem-like properties and decreases spontaneous differentiation in human mesenchymal stem cell lines. J. Biomed. Sci. 2010, 17, 64.


Okada, M.; Kim, H. W.; Matsu-Ura, K.; Wang, Y. G.; Xu, M. F.; Ashraf, M. Abrogation of age-induced MicroRNA-195 rejuvenates the senescent mesenchymal stem cells by reactivating telomerase. Stem Cells 2016, 34, 148–159.


Lee, W. C.; Kim, D. Y.; Kim, M. J.; Lee, H. J.; Bharti, D.; Lee, S. H.; Kang, Y. H.; Rho, G. J.; Jeon, B. G. Delay of cell growth and loss of stemness by inhibition of reverse transcription in human mesenchymal stem cells derived from dental tissue. Anim. Cells Syst. (Seoul) 2019, 23, 335–345.


Gordon, D. M.; Santos, J. H. The emerging role of telomerase reverse transcriptase in mitochondrial DNA metabolism. J. Nucleic Acids 2010, 2010, 390791.


Haendeler, J.; Dröose, S.; Büchner, N.; Jakob, S.; Altschmied, J.; Goy, C.; Spyridopoulos, I.; Zeiher, A. M.; Brandt, U.; Dimmeler, S. Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler. Thromb. Vasc. Biol. 2009, 29, 929–935.


Ahmed, S.; Passos, J. F.; Birket, M. J.; Beckmann, T.; Brings, S.; Peters, H.; Birch-Machin, M. A.; von Zglinicki, T.; Saretzki, G. Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. J. Cell Sci. 2008, 121, 1046–1053.


Sharma, N. K.; Reyes, A.; Green, P.; Caron, M. J.; Bonini, M. G.; Gordon, D. M.; Holt, I. J.; Santos, J. H. Human telomerase acts as a hTR-independent reverse transcriptase in mitochondria. Nucleic Acids Res. 2012, 40, 712–725.


Ale-Agha, N.; Jakobs, P.; Goy, C.; Zurek, M.; Rosen, J.; Dyballa-Rukes, N.; Metzger, S.; Greulich, J.; Ameln, F. V.; Eckermann, O. et al. Mitochondrial telomerase reverse transcriptase protects from myocardial ischemia/reperfusion injury by improving complex Ⅰ composition and function. Circulation 2021, 144, 1876–1890.


Trachana, V.; Petrakis, S.; Fotiadis, Z.; Siska, E. K.; Balis, V.; Gonos, E. S.; Kaloyianni, M.; Koliakos, G. Human mesenchymal stem cells with enhanced telomerase activity acquire resistance against oxidative stress-induced genomic damage. Cytotherapy 2017, 19, 808–820.


Chen, C.; Akiyama, K.; Yamaza, T.; You, Y. O.; Xu, X. T.; Li, B.; Zhao, Y. M.; Shi, S. T. Telomerase governs immunomodulatory properties of mesenchymal stem cells by regulating FAS ligand expression. EMBO Mol. Med. 2014, 6, 322–334.


Rodriguez, R.; Rosu-Myles, M.; Aráuzo-Bravo, M.; Horrillo, A.; Pan, Q. W.; Gonzalez-Rey, E.; Delgado, M.; Menendez, P. Human bone marrow stromal cells lose immunosuppressive and anti-inflammatory properties upon oncogenic transformation. Stem Cell Rep. 2014, 3, 606–619.


Beckenkamp, L. R.; da Fontoura, D. M. S.; Korb, V. G.; de Campos, R. P.; Onzi, G. R.; Iser, I. C.; Bertoni, A. P. S.; Sévigny, J.; Lenz, G.; Wink, M. R. Immortalization of mesenchymal stromal cells by TERT affects adenosine metabolism and impairs their immunosuppressive capacity. Stem Cell Rev. Rep. 2020, 16, 776–791.


Pignolo, R. J.; Suda, R. K.; McMillan, E. A.; Shen, J.; Lee, S. H.; Choi, Y.; Wright, A. C.; Johnson, F. B. Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis. Aging Cell 2008, 7, 23–31.


Wang, H. T.; Chen, Q. J.; Lee, S. H.; Choi, Y.; Johnson, F. B.; Pignolo, R. J. Impairment of osteoblast differentiation due to proliferation-independent telomere dysfunction in mouse models of accelerated aging. Aging Cell 2012, 11, 704–713.


Saeed, H.; Abdallah, B. M.; Ditzel, N.; Catala-Lehnen, P.; Qiu, W. M.; Amling, M.; Kassem, M. Telomerase-deficient mice exhibit bone loss owing to defects in osteoblasts and increased osteoclastogenesis by inflammatory microenvironment. J. Bone Miner. Res. 2011, 26, 1494–1505.


Saeed, H.; Iqtedar, M. Aberrant gene expression profiles, during in vitro osteoblast differentiation, of telomerase deficient mouse bone marrow stromal stem cells (mBMSCs). J. Biomed. Sci. 2015, 22, 11.


Li, C.; Wei, G. J.; Gu, Q.; Wang, Q.; Tao, S. Q.; Xu, L. Proliferation and differentiation of rat osteoporosis mesenchymal stem cells (MSCs) after telomerase reverse transcriptase (TERT) transfection. Med. Sci. Monit. 2015, 21, 845–854.


Machado, C. B.; Correa, C. R.; Medrado, G. C.; Leite, M. F.; Goes, A. M. Ectopic expression of telomerase enhances osteopontin and osteocalcin expression during osteogenic differentiation of human mesenchymal stem cells from elder donors. J. Stem Cells Regen. Med. 2009, 5, 49–57.


Saeed, H.; Qiu, W. M.; Li, C.; Flyvbjerg, A.; Abdallah, B. M.; Kassem, M. Telomerase activity promotes osteoblast differentiation by modulating IGF-signaling pathway. Biogerontology 2015, 16, 733–745.


Zhu, X.; Zhou, L.; Liu, Z.; Chen, X.; Wei, L.; Zhang, Z.; Liu, Y.; Zhu, Y.; Wang, Y.; Yang, X. et al. Telomerase enhances osteogenic ifferentiation of sheep bone marrow mesenchymal stem cells (BMSCs) by up-regulating PI3K/Akt pathway in vitro. Pol. J. Vet. Sci. 2020, 23, 359–372.


Mirsaidi, A.; Kleinhans, K. N.; Rimann, M.; Tiaden, A. N.; Stauber, M.; Rudolph, K. L.; Richards, P. J. Telomere length, telomerase activity and osteogenic differentiation are maintained in adipose-derived stromal cells from senile osteoporotic SAMP6 mice. J. Tissue Eng. Regen. Med. 2012, 6, 378–390.


Kim, M.; Kim, C.; Choi, Y. S.; Kim, M.; Park, C.; Suh, Y. Age-related alterations in mesenchymal stem cells related to shift in differentiation from osteogenic to adipogenic potential: Implication to age-associated bone diseases and defects. Mech. Ageing Dev. 2012, 133, 215–225.


Prawitt, J.; Niemeier, A.; Kassem, M.; Beisiegel, U.; Heeren, J. Characterization of lipid metabolism in insulin-sensitive adipocytes differentiated from immortalized human mesenchymal stem cells. Exp. Cell Res. 2008, 314, 814–824.


Kulebyakin, K.; Tyurin-Kuzmin, P.; Efimenko, A.; Voloshin, N.; Kartoshkin, A.; Karagyaur, M.; Grigorieva, O.; Novoseletskaya, E.; Sysoeva, V.; Makarevich, P. et al. Decreased insulin sensitivity in telomerase-immortalized mesenchymal stem cells affects efficacy and outcome of adipogenic differentiation in vitro. Front. Cell Dev. Biol. 2021, 9, 662078.


Masnikov, D.; Stafeev, I.; Michurina, S.; Zubkova, E.; Mamontova, E.; Ratner, E.; Menshikov, M.; Parfyonova, Y. hTERT-immortalized adipose-derived stem cell line ASC52Telo demonstrates limited potential for adipose biology research. Anal. Biochem. 2021, 628, 114268.


Scharstuhl, A.; Schewe, B.; Benz, K.; Gaissmaier, C.; Bühring, H. J.; Stoop, R. Chondrogenic potential of human adult mesenchymal stem cells is independent of age or osteoarthritis etiology. Stem Cells 2007, 25, 3244–3251.


Jiang, T. M.; Xu, G. J.; Wang, Q. Y.; Yang, L. H.; Zheng, L.; Zhao, J. M.; Zhang, X. D. Correction: In vitro expansion impaired the stemness of early passage mesenchymal stem cells for treatment of cartilage defects. Cell Death Dis. 2019, 10, 716.


Dale, T. P.; de Castro, A.; Kuiper, N. J.; Parkinson, E. K.; Forsyth, N. R. Immortalisation with hTERT impacts on sulphated glycosaminoglycan secretion and immunophenotype in a variable and cell specific manner. PLoS One 2015, 10, e0133745.


Dale, T. P.; Forsyth, N. R. Ectopic telomerase expression fails to maintain chondrogenic capacity in three-dimensional cultures of clinically relevant cell types. Biores. Open Access 2018, 7, 10–24.


Salazar-Noratto, G. E.; Luo, G. T.; Denoeud, C.; Padrona, M.; Moya, A.; Bensidhoum, M.; Bizios, R.; Potier, E.; Logeart-Avramoglou, D.; Petite, H. Understanding and leveraging cell metabolism to enhance mesenchymal stem cell transplantation survival in tissue engineering and regenerative medicine applications. Stem Cells 2020, 38, 22–33.


Böcker, W.; Yin, Z. H.; Drosse, I.; Haasters, F.; Rossmann, O.; Wierer, M.; Popov, C.; Locher, M.; Mutschler, W.; Docheva, D. et al. Introducing a single-cell-derived human mesenchymal stem cell line expressing hTERT after lentiviral gene transfer. J. Cell. Mol. Med. 2008, 12, 1347–1359.


Wei, L. L.; Gao, K.; Liu, P. Q.; Lu, X. F.; Li, S. F.; Cheng, J. Q.; Li, Y. P.; Lu, Y. R. Mesenchymal stem cells from Chinese Guizhou minipig by hTERT gene transfection. Transplant. Proc. 2008, 40, 547–550.


Gao, K.; Lu, Y. R.; Wei, L. L.; Lu, X. F.; Li, S. F.; Wan, L.; Li, Y. P.; Cheng, J. Q. Immortalization of mesenchymal stem cells from bone marrow of rhesus monkey by transfection with human telomerase reverse transcriptase gene. Transplant. Proc. 2008, 40, 634–637.


Huang, G. P.; Pan, Z. J.; Huang, J. P.; Yang, J. F.; Guo, C. J.; Wang, Y. G.; Zheng, Q.; Chen, R.; Xu, Y. L.; Wang, G. Z. et al. Proteomic analysis of human bone marrow mesenchymal stem cells transduced with human telomerase reverse transcriptase gene during proliferation. Cell Prolif. 2008, 41, 625–644.


Huang, G. P.; Zheng, Q.; Sun, J.; Guo, C. J.; Yang, J. F.; Chen, R.; Xu, Y. L.; Wang, G. Z.; Shen, D.; Pan, Z. J. et al. Stabilization of cellular properties and differentiation mutilpotential of human mesenchymal stem cells transduced with hTERT gene in a long-term culture. J. Cell. Biochem. 2008, 103, 1256–1269.


Piper, S. L.; Wang, M. Q.; Yamamoto, A.; Malek, F.; Luu, A.; Kuo, A. C.; Kim, H. T. Inducible immortality in hTERT-human mesenchymal stem cells. J. Orthop. Res. 2012, 30, 1879–1885.


Liu, T. M. Ng, W. M.; Tan, H. S.; Vinitha, D.; Yang, Z.; Fan, J. B.; Zou, Y.; Hui, J. H.; Lee, E. H.; Lim, B. Molecular basis of immortalization of human mesenchymal stem cells by combination of p53 knockdown and human telomerase reverse transcriptase overexpression. Stem Cells Dev. 2013, 22, 268–278.


Skårn, M.; Noordhuis, P.; Wang, M. Y.; Veuger, M.; Kresse, S. H.; Egeland, E. V.; Micci, F.; Namløs, H. M.; Håkelien, A. M.; Olafsrud, S. M. et al. Generation and characterization of an immortalized human mesenchymal stromal cell line. Stem Cells Dev. 2014, 23, 2377–2389.


Piñeiro-Ramil, M.; Sanjurjo-Rodríguez, C.; Rodríguez-Fernández, S.; Castro-Viñuelas, R.; Hermida-Gómez, T.; Blanco-García, F. J.; Fuentes-Boquete, I.; Díaz-Prado, S. Generation of mesenchymal cell lines derived from aged donors. Int. J. Mol. Sci. 2021, 22, 10667.


Bischoff, D. S.; Makhijani, N. S.; Yamaguchi, D. T. Constitutive expression of human telomerase enhances the proliferation potential of human mesenchymal stem cells. Biores. Open Access 2012, 1, 273–279.


Yalvaç, M. E.; Yilmaz, A.; Mercan, D.; Aydin, S.; Dogan, A.; Arslan, A.; Demir, Z.; Salafutdinov, I. I.; Shafigullina, A. K.; Sahin, F. et al. Differentiation and neuro-protective properties of immortalized human tooth germ stem cells. Neurochem. Res. 2011, 36, 2227–2235.


Yao, C. L.; Hwang, S. M. Immortalization of human mesenchymal stromal cells with telomerase and red fluorescence protein expression. Methods Mol. Biol. 2012, 879, 471–478.


Wolbank, S.; Stadler, G.; Peterbauer, A.; Gillich, A.; Karbiener, M.; Streubel, B.; Wieser, M.; Katinger, H.; van Griensven, M.; Redl, H. et al. Telomerase immortalized human amnion- and adipose-derived mesenchymal stem cells: Maintenance of differentiation and immunomodulatory characteristics. Tissue Eng. Part A 2009, 15, 1843–1854.


Zhou, K. X.; Koike, C.; Yoshida, T.; Okabe, M.; Fathy, M.; Kyo, S.; Kiyono, T.; Saito, S.; Nikaido, T. Establishment and characterization of immortalized human amniotic epithelial cells. Cell. Reprogram. 2013, 15, 55–67.


Teng, Z.; Yoshida, T.; Okabe, M.; Toda, A.; Higuchi, O.; Nogami, M.; Yoneda, N.; Zhou, K. X.; Kyo, S.; Kiyono, T. et al. Establishment of immortalized human amniotic mesenchymal stem cells. Cell Transplant. 2013, 22, 267–278.

Wongkajornsilp, A.; Sa-Ngiamsuntorn, K.; Hongeng, S. Development of immortalized hepatocyte-like cells from hMSCs. In Liver Stem Cells. Ochiya, T., Ed.; Springer: New York, 2012; pp 73–87.

Cao, H.; Chu, Y.; Zhu, H.; Sun, J.; Pu, Y.; Gao, Z.; Yang, C.; Peng, S.; Dou, Z.; Hua, J. Characterization of immortalized mesenchymal stem cells derived from foetal porcine pancreas. Cell Prolif. 2011, 44, 19–32.


Goradel, N. H.; Hour, F. G.; Negahdari, B.; Malekshahi, Z. V.; Hashemzehi, M.; Masoudifar, A.; Mirzaei, H. Stem cell therapy: A new therapeutic option for cardiovascular diseases. J. Cell. Biochem. 2018, 119, 95–104.


Bagno, L.; Hatzistergos, K. E.; Balkan, W.; Hare, J. M. Mesenchymal stem cell-based therapy for cardiovascular disease: Progress and challenges. Mol. Ther. 2018, 26, 1610–1623.


Balducci, L.; Blasi, A.; Saldarelli, M.; Soleti, A.; Pessina, A.; Bonomi, A.; Coccè, V.; Dossena, M.; Tosetti, V.; Ceserani, V. et al. Immortalization of human adipose-derived stromal cells: Production of cell lines with high growth rate, mesenchymal marker expression and capability to secrete high levels of angiogenic factors. Stem Cell Res. Ther. 2014, 5, 63.


Burns, J. S.; Kristiansen, M.; Kristensen, L. P.; Larsen, K. H.; Nielsen, M. O.; Christiansen, H.; Nehlin, J.; Andersen, J. S.; Kassem, M. Decellularized matrix from tumorigenic human mesenchymal stem cells promotes neovascularization with galectin-1 dependent endothelial interaction. PLoS One 2011, 6, e21888.


Madonna, R.; Taylor, D. A.; Geng, Y. J.; Caterina, R. D.; Shelat, H.; Perin, E. C.; Willerson, J. T. Transplantation of mesenchymal cells rejuvenated by the overexpression of telomerase and myocardin promotes revascularization and tissue repair in a murine model of hindlimb ischemia. Circ. Res. 2013, 113, 902–914.


Madonna, R.; Angelucci, S.; Di Giuseppe, F.; Doria, V.; Giricz, Z.; Görbe, A.; Ferdinandy, P.; De Caterina, R. Proteomic analysis of the secretome of adipose tissue-derived murine mesenchymal cells overexpressing telomerase and myocardin. J. Mol. Cell. Cardiol. 2019, 131, 171–186.


Madonna, R.; Pieragostino, D.; Rossi, C.; Guarnieri, S.; Nagy, C. T.; Giricz, Z.; Ferdinandy, P.; Del Boccio, P.; Mariggiò, M. A.; Geng, Y. J. et al. Transplantation of telomerase/myocardin-co-expressing mesenchymal cells in the mouse promotes myocardial revascularization and tissue repair. Vascul. Pharmacol. 2020, 135, 106807.


Madonna, R.; Guarnieri, S.; Kovácsházi, C.; Görbe, A.; Giricz, Z.; Geng, Y. J.; Mariggiò, M. A.; Ferdinandy, P.; De Caterina, R. Telomerase/myocardin expressing mesenchymal cells induce survival and cardiovascular markers in cardiac stromal cells undergoing ischaemia/reperfusion. J. Cell. Mol. Med. 2021, 25, 5381–5390.


Le, T. Y. L.; Pickett, H. A.; Yang, A.; Ho, J. W. K.; Thavapalachandran, S.; Igoor, S.; Yang, S. F.; Farraha, M.; Voges, H. K.; Hudson, J. E. et al. Enhanced cardiac repair by telomerase reverse transcriptase over-expression in human cardiac mesenchymal stromal cells. Sci. Rep. 2019, 9, 10579.


Luo, L. H.; He, Y.; Wang, X. Y.; Key, B.; Lee, B. H.; Li, H. Q.; Ye, Q. S. Potential roles of dental pulp stem cells in neural regeneration and repair. Stem Cells Int. 2018, 2018, 1731289.


Li, J. Y.; Liu, W. D.; Yao, W. C. Immortalized human bone marrow derived stromal cells in treatment of transient cerebral ischemia in rats. J. Alzheimers Dis. 2019, 69, 871–880.


Honma, T.; Honmou, O.; Iihoshi, S.; Harada, K.; Houkin, K.; Hamada, H.; Kocsis, J. D. Intravenous infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Exp. Neurol. 2006, 199, 56–66.


Zhao, F. Y.; Qu, Y.; Liu, H. T.; Du, B. W.; Mu, D. Z. Umbilical cord blood mesenchymal stem cells co-modified by TERT and BDNF: A novel neuroprotective therapy for neonatal hypoxic-ischemic brain damage. Int. J. Dev. Neurosci. 2014, 38, 147–154.


Eizirik, D. L.; Pasquali, L.; Cnop, M. Pancreatic β-cells in type 1 and type 2 diabetes mellitus: Different pathways to failure. Nat. Rev. Endocrinol. 2020, 16, 349–362.


Cheng, F. F.; Carroll, L.; Joglekar, M. V.; Januszewski, A. S.; Wong, K. K.; Hardikar, A. A.; Jenkins, A. J.; Ma, R. C. W. Diabetes, metabolic disease, and telomere length. Lancet Diabetes Endocrinol. 2021, 9, 117–126.


Khatri, R.; Mazurek, S.; Petry, S. F.; Linn, T. Mesenchymal stem cells promote pancreatic β-cell regeneration through downregulation of FoxO1 pathway. Stem Cell Res. Ther. 2020, 11, 497.


Luna, G. L. F.; Oehlmeyer, T. L.; Brandão, G.; Brassolatti, P.; Tosta, J.; Goto, L. S.; de Avó, L.; de Oliveira Leal, A. M. Use of human bone marrow mesenchymal stem cells immortalized by the expression of telomerase in wound healing in diabetic rats. Braz. J. Med. Biol. Res. 2021, 54, e11352.


Nakahara, H.; Misawa, H.; Hayashi, T.; Kondo, E.; Yuasa, T.; Kubota, Y.; Seita, M.; Kawamoto, H.; Hassan, W. A. R. A.; Hassan, R. A. R. A. et al. Bone repair by transplantation of hTERT-immortalized human mesenchymal stem cells in mice. Transplantation 2009, 88, 346–353.


Gómez-Ferrer, M.; Amaro-Prellezo, E.; Dorronsoro, A.; Sánchez-Sánchez, R.; Vicente, Á.; Cosín-Roger, J.; Barrachina, M. D.; Baquero, M. C.; Valencia, J.; Sepúlveda, P. HIF-overexpression and pro-inflammatory priming in human mesenchymal stromal cells improves the healing properties of extracellular vesicles in experimental crohn's disease. Int. J. Mol. Sci. 2021, 22, 11269.


Wu, H. H.; Zhou, Y.; Tabata, Y.; Gao, J. Q. Mesenchymal stem cell-based drug delivery strategy: From cells to biomimetic. J. Control. Release 2019, 294, 102–113.


An, K.; Liu, H. P.; Zhong, X. L.; Deng, D. Y. B.; Zhang, J. J.; Liu, Z. H. hTERT-immortalized bone mesenchymal stromal cells expressing rat galanin via a single tetracycline-inducible lentivirus system. Stem Cells Int. 2017, 2017, 6082684.


Hade, M. D.; Suire, C. N.; Suo, Z. C. Mesenchymal stem cell-derived exosomes: Applications in regenerative medicine. Cells 2021, 10, 1959.


Chen, T. S.; Arslan, F.; Yin, Y. J.; Tan, S. S.; Lai, R. C.; Choo, A. B. H.; Padmanabhan, J.; Lee, C. N.; de Kleijn, D. P. V.; Lim, S. K. Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J. Transl. Med. 2011, 9, 47.


Cocce, V.; Balducci, L.; Falchetti, M. L.; Pascucci, L.; Ciusani, E.; Brini, A. T.; Sisto, F.; Piovani, G.; Alessandri, G.; Parati, E. et al. Fluorescent immortalized human adipose derived stromal cells (hASCs-TS/GFP+) for studying cell drug delivery mediated by microvesicles. Anti-Cancer Agents Med. Chem. 2017, 17, 1578–1585.


Gomzikova, M. O.; James, V.; Rizvanov, A. A. Mitochondria donation by mesenchymal stem cells: Current understanding and mitochondria transplantation strategies. Front. Cell Dev. Biol. 2021, 9, 653322.


Popov, L. D. One step forward: Extracellular mitochondria transplantation. Cell Tissue Res. 2021, 384, 607–612.


Carlone, D. L.; Riba-Wolman, R. D.; Deary, L. T.; Tovaglieri, A.; Jiang, L. J.; Ambruzs, D. M.; Mead, B. E.; Shah, M. S.; Lengner, C. J.; Jaenisch, R. et al. Telomerase expression marks transitional growth-associated skeletal progenitor/stem cells. Stem Cells 2021, 39, 296–305.


Deane, J. A.; Ong, Y. R.; Cain, J. E.; Jayasekara, W. S. N.; Tiwari, A.; Carlone, D. L.; Watkins, D. N.; Breault, D. T.; Gargett, C. E. The mouse endometrium contains epithelial, endothelial and leucocyte populations expressing the stem cell marker telomerase reverse transcriptase. Mol. Hum. Reprod. 2016, 22, 272–284.


Richardson, G. D.; Breault, D.; Horrocks, G.; Cormack, S.; Hole, N.; Owens, W. A. Telomerase expression in the mammalian heart. FASEB J. 2012, 26, 4832–4840.


Hung, C. J. Yao, C. L.; Cheng, F. C.; Wu, M. L.; Wang, T. H.; Hwang, S. M. Establishment of immortalized mesenchymal stromal cells with red fluorescence protein expression for in vivo transplantation and tracing in the rat model with traumatic brain injury. Cytotherapy 2010, 12, 455–465.


Wang, J. S.; Wu, L.; Ren, J. S.; Qu, X. G. Visualizing human telomerase activity with primer-modified Au nanoparticles. Small 2012, 8, 259–264.


Ling, P. H.; Qian, C. H.; Yu, J. J.; Gao, F. Artificial nanozyme based on platinum nanoparticles anchored metal-organic frameworks with enhanced electrocatalytic activity for detection of telomeres activity. Biosens. Bioelectron. 2020, 149, 111838.


Qian, R. C.; Ding, L.; Ju, H. X. Switchable fluorescent imaging of intracellular telomerase activity using telomerase-responsive mesoporous silica nanoparticle. J. Am. Chem. Soc. 2013, 135, 13282–13285.


Chenab, K. K.; Eivazzadeh-Keihan, R.; Maleki, A.; Pashazadeh-Panahi, P.; Hamblin, M. R.; Mokhtarzadeh, A. Biomedical applications of nanoflares: Targeted intracellular fluorescence probes. Nanomed. : Nanotechnol., Biol. Med. 2019, 17, 342–358.


Dong, F. Y.; Feng, E. D.; Zheng, T. T.; Tian, Y. In situ synthesized silver nanoclusters for tracking the role of telomerase activity in the differentiation of mesenchymal stem cells to neural stem cells. ACS Appl. Mater. Interfaces 2018, 10, 2051–2057.


Park, H. H.; Lee, K. Y.; Park, D. W.; Choi, N. Y.; Lee, Y. J.; Son, J. W.; Kim, S.; Moon, C.; Kim, H. W.; Rhyu, I. J. et al. Tracking and protection of transplanted stem cells using a ferrocenecarboxylic acid-conjugated peptide that mimics hTERT. Biomaterials 2018, 155, 80–91.


Ferguson, L. R.; Chen, H.; Collins, A. R.; Connell, M.; Damia, G.; Dasgupta, S.; Malhotra, M.; Meeker, A. K.; Amedei, A.; Amin, A. et al. Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. Semin. Cancer Biol. 2015, 35 Suppl 1, S5–S24.


Anvar, L. H.; Hosseini-Asl, S.; Mohammadzadeh-Vardin, M.; Sagha, M. The telomerase activity of selenium-induced human umbilical cord mesenchymal stem cells is associated with different levels of c-Myc and p53 expression. DNA Cell Biol. 2017, 36, 34–41.


Radomska, D.; Czarnomysy, R.; Radomski, D.; Bielawska, A.; Bielawski, K. Selenium as a bioactive micronutrient in the human diet and its cancer chemopreventive activity. Nutrients 2021, 13, 1649.


Wang, J.; Zhao, H. H.; Xu, Z. L.; Cheng, X. X. Zinc dysregulation in cancers and its potential as a therapeutic target. Cancer Biol. Med. 2020, 17, 612–625.


Farahzadi, R.; Fathi, E.; Mesbah-Namin, S. A.; Zarghami, N. Zinc sulfate contributes to promote telomere length extension via increasing telomerase gene expression, telomerase activity and change in the TERT gene promoter CpG island methylation status of human adipose-derived mesenchymal stem cells. PLoS One 2017, 12, e0188052.

Publication history
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Publication history

Received: 02 June 2022
Accepted: 01 July 2022
Published: 08 September 2022
Issue date: December 2022


© The Author(s) 2022. Nano TransMed published by Tsinghua University Press.


This work was supported by the National Natural Science Foundation of China (No. 81871503 from Qingsong Ye) and Chutian Researcher Project (No. X22020024 from Yan He).

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