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Stem Cell Reviews and Reports

, Volume 15, Issue 4, pp 463–473 | Cite as

Enhancing the Therapeutic Potential of Mesenchymal Stem Cells with the CRISPR-Cas System

  • Daniel Mendes Filho
  • Patrícia de Carvalho Ribeiro
  • Lucas Felipe Oliveira
  • Ana Luiza Romero Terra dos Santos
  • Ricardo Cambraia ParreiraEmail author
  • Mauro Cunha Xavier Pinto
  • Rodrigo Ribeiro Resende
Article

Abstract

Mesenchymal stem cells (MSCs), also known as multipotent mesenchymal stromal stem cells, are found in the perivascular space of several tissues. These cells have been subject of intense research in the last decade due to their low teratogenicity, as well as their ability to differentiate into mature cells and to secrete immunomodulatory and trophic factors. However, they usually promote only a modest benefit when transplanted in experimental disease models, one of the limitations for their clinical application. The CRISPR-Cas system, in turn, is highlighted as a simple and effective tool for genetic engineering. This system was tested in clinical trials over a relatively short period of time after establishing its applicability to the edition of the mammalian cell genome. Similar to the research evolution in MSCs, the CRISPR-Cas system demonstrated inconsistencies that limited its clinical application. In this review, we outline the evolution of MSC research and its applicability, and the progress of the CRISPR-Cas system from its discovery to the most recent clinical trials. We also propose perspectives on how the CRISPR-Cas system may improve the therapeutic potential of MSCs, making it more beneficial and long lasting.

Keywords

CRISPR-Cas Mesenchymal stem cells Mesenchymal stromal cells Genetic engineering Cell therapy 

Notes

Funding

This work was supported by National Council for Scientific and Technological Development (CNPq, Brazil).

References

  1. 1.
    da Silva Meirelles, L., Caplan, A. I., & Nardi, N. B. (2008). In search of the in vivo identity of mesenchymal stem cells. Stem Cells, 26(9), 2287–2299.Google Scholar
  2. 2.
    Caplan, A. I. (2017). Mesenchymal stem cells: Time to change the name. Stem Cells Translational Medicine., 6(6), 1445–1451.Google Scholar
  3. 3.
    Rose, R. A., Jiang, H., Wang, X., Helke, S., Tsoporis, J. N., Gong, N., et al. (2008). Bone marrow-derived mesenchymal stromal cells express cardiac-specific markers, retain the stromal phenotype, and do not become functional cardiomyocytes in vitro. Stem Cells, 26(11), 2884–2892.Google Scholar
  4. 4.
    Pijnappels, D. A., Schalij, M. J., Ramkisoensing, A. A., van Tuyn, J., de Vries, A. A., van der Laarse, A., et al. (2008). Forced alignment of mesenchymal stem cells undergoing cardiomyogenic differentiation affects functional integration with cardiomyocyte cultures. Circulation Research., 103(2), 167–176.Google Scholar
  5. 5.
    Mendivil-Perez, M., Velez-Pardo, C., & Jimenez-Del-Rio, M. (2019). Direct transdifferentiation of human Wharton's jelly mesenchymal stromal cells into cholinergic-like neurons. Journal of Neuroscience Methods., 312, 126–138.Google Scholar
  6. 6.
    Haragopal, H., Yu, D., Zeng, X., Kim, S. W., Han, I. B., Ropper, A. E., et al. (2015). Stemness enhancement of human neural stem cells following bone marrow MSC coculture. Cell Transplantation., 24(4), 645–659.Google Scholar
  7. 7.
    Mojica, F. J., Juez, G., & Rodriguez-Valera, F. (1993). Transcription at different salinities of Haloferax mediterranei sequences adjacent to partially modified PstI sites. Molecular Microbiology., 9(3), 613–621.Google Scholar
  8. 8.
    Barrangou, R., Fremaux, C., Deveau, H., Richards, M., Boyaval, P., Moineau, S., et al. (2007). CRISPR provides acquired resistance against viruses in prokaryotes. Science., 315(5819), 1709–1712.Google Scholar
  9. 9.
    Brouns, S. J., Jore, M. M., Lundgren, M., Westra, E. R., Slijkhuis, R. J., Snijders, A. P., et al. (2008). Small CRISPR RNAs guide antiviral defense in prokaryotes. Science., 321(5891), 960–964.Google Scholar
  10. 10.
    Barrangou, R., & Marraffini, L. A. (2014). CRISPR-Cas systems: Prokaryotes upgrade to adaptive immunity. Molecular Cell, 54(2), 234–244.Google Scholar
  11. 11.
    Doudna, J. A., & Charpentier, E. (2014). Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science., 346(6213), 1258096.Google Scholar
  12. 12.
    Deltcheva, E., Chylinski, K., Sharma, C. M., Gonzales, K., Chao, Y., Pirzada, Z. A., et al. (2011). CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. Nature., 471(7340), 602–607.Google Scholar
  13. 13.
    Pennisi, E. (2013). The CRISPR craze. Science., 341(6148), 833–836.Google Scholar
  14. 14.
    Makarova, K. S., Wolf, Y. I., Alkhnbashi, O. S., Costa, F., Shah, S. A., Saunders, S. J., et al. (2015). An updated evolutionary classification of CRISPR-Cas systems. Nature Reviews Microbiology., 13(11), 722–736.Google Scholar
  15. 15.
    Bolotin, A., Quinquis, B., Sorokin, A., & Ehrlich, S. D. (2005). Clustered regularly interspaced short palindrome repeats (CRISPRs) have spacers of extrachromosomal origin. Microbiology., 151(Pt 8, 2551–2561.Google Scholar
  16. 16.
    Marraffini, L. A., & Sontheimer, E. J. (2008). CRISPR interference limits horizontal gene transfer in staphylococci by targeting DNA. Science., 322(5909), 1843–1845.Google Scholar
  17. 17.
    Lander, E. S. (2016). The heroes of CRISPR. Cell., 164(1–2), 18–28.Google Scholar
  18. 18.
    Chen, K. Y., & Knoepfler, P. S. (2016). To CRISPR and beyond: The evolution of genome editing in stem cells. Regenerative Medicine., 11(8), 801–816.Google Scholar
  19. 19.
    Cho, S. W., Kim, S., Kim, J. M., & Kim, J. S. (2013). Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. Nature Biotechnology., 31(3), 230–232.Google Scholar
  20. 20.
    Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., et al. (2013). Multiplex genome engineering using CRISPR/Cas systems. Science., 339(6121), 819–823.Google Scholar
  21. 21.
    Fu, Y., Foden, J. A., Khayter, C., Maeder, M. L., Reyon, D., Joung, J. K., et al. (2013). High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nature Biotechnology., 31(9), 822–826.Google Scholar
  22. 22.
    Jinek, M., East, A., Cheng, A., Lin, S., Ma, E., & Doudna, J. (2013). RNA-programmed genome editing in human cells. eLife., 2, e00471.Google Scholar
  23. 23.
    Cong, L., & Zhang, F. (2015). Genome engineering using CRISPR-Cas9 system. Methods in Molecular Biology., 1239, 197–217.Google Scholar
  24. 24.
    Kim, S., Kim, D., Cho, S. W., Kim, J., & Kim, J. S. (2014). Highly efficient RNA-guided genome editing in human cells via delivery of purified Cas9 ribonucleoproteins. Genome Research, 24(6), 1012–1019.Google Scholar
  25. 25.
    Sander, J. D., & Joung, J. K. (2014). CRISPR-Cas systems for editing, regulating and targeting genomes. Nature Biotechnology., 32(4), 347–355.Google Scholar
  26. 26.
    Maeder, M. L., & Gersbach, C. A. (2016). Genome-editing Technologies for Gene and Cell Therapy. Molecular Therapy : the Journal of the American Society of Gene Therapy., 24(3), 430–446.Google Scholar
  27. 27.
    Mollanoori, H., & Teimourian, S. (2018). Therapeutic applications of CRISPR/Cas9 system in gene therapy. Biotechnology Letters, 40(6), 907–914.Google Scholar
  28. 28.
    Jiang, F., & Doudna, J. A. (2017). CRISPR-Cas9 structures and mechanisms. Annual Review of Biophysics, 46, 505–529.Google Scholar
  29. 29.
    Foss, D. V., Hochstrasser, M. L., & Wilson, R. C. (2019). Clinical applications of CRISPR-based genome editing and diagnostics. Transfusion., 59, 1389–1399.Google Scholar
  30. 30.
    Baylis, F., & McLeod, M. (2017). First-in-human phase 1 CRISPR gene editing Cancer trials: Are we ready? Current Gene Therapy., 17(4), 309–319.Google Scholar
  31. 31.
    Brokowski, C., & Adli, M. (2019). CRISPR ethics: Moral considerations for applications of a powerful tool. Journal of Molecular Biology., 431(1), 88–101.Google Scholar
  32. 32.
    Martinez-Lage, M., Puig-Serra, P., Menendez, P., Torres-Ruiz, R., & Rodriguez-Perales, S. (2018). CRISPR/Cas9 for Cancer therapy: Hopes and challenges. Biomedicines., 6(4).Google Scholar
  33. 33.
    Soppe, J. A., & Lebbink, R. J. (2017). Antiviral Goes viral: Harnessing CRISPR/Cas9 to combat viruses in humans. Trends in Microbiology., 25(10), 833–850.Google Scholar
  34. 34.
    Xie, C., Zhang, Y. P., Song, L., Luo, J., Qi, W., Hu, J., et al. (2016). Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome. Cell Research., 26(10), 1099–1111.Google Scholar
  35. 35.
    Liu, Y., Yang, Y., Kang, X., Lin, B., Yu, Q., Song, B., et al. (2017). One-step Biallelic and Scarless correction of a beta-thalassemia mutation in patient-specific iPSCs without drug selection. Molecular Therapy Nucleic acids., 6, 57–67.Google Scholar
  36. 36.
    Park, C. Y., Kim, D. H., Son, J. S., Sung, J. J., Lee, J., Bae, S., et al. (2015). Functional correction of large factor VIII gene chromosomal inversions in hemophilia a patient-derived iPSCs using CRISPR-Cas9. Cell Stem Cell, 17(2), 213–220.Google Scholar
  37. 37.
    Chang, C. W., Lai, Y. S., Westin, E., Khodadadi-Jamayran, A., Pawlik, K. M., Lamb, L. S., Jr., et al. (2015). Modeling human severe combined immunodeficiency and correction by CRISPR/Cas9-enhanced gene targeting. Cell Reports, 12(10), 1668–1677.Google Scholar
  38. 38.
    Pankowicz, F. P., Barzi, M., Legras, X., Hubert, L., Mi, T., Tomolonis, J. A., et al. (2016). Reprogramming metabolic pathways in vivo with CRISPR/Cas9 genome editing to treat hereditary tyrosinaemia. Nature Communications, 7, 12642.Google Scholar
  39. 39.
    Koo, T., Yoon, A. R., Cho, H. Y., Bae, S., Yun, C. O., & Kim, J. S. (2017). Selective disruption of an oncogenic mutant allele by CRISPR/Cas9 induces efficient tumor regression. Nucleic Acids Research., 45(13), 7897–7908.Google Scholar
  40. 40.
    Li, H. L., Fujimoto, N., Sasakawa, N., Shirai, S., Ohkame, T., Sakuma, T., et al. (2015). Precise correction of the dystrophin gene in duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9. Stem Cell Reports., 4(1), 143–154.Google Scholar
  41. 41.
    Wang, L., Yi, F., Fu, L., Yang, J., Wang, S., Wang, Z., et al. (2017). CRISPR/Cas9-mediated targeted gene correction in amyotrophic lateral sclerosis patient iPSCs. Protein & Cell., 8(5), 365–378.Google Scholar
  42. 42.
    Firth, A. L., Menon, T., Parker, G. S., Qualls, S. J., Lewis, B. M., Ke, E., et al. (2015). Functional gene correction for cystic fibrosis in lung epithelial cells generated from patient iPSCs. Cell Reports, 12(9), 1385–1390.Google Scholar
  43. 43.
    Hainzl, S., Peking, P., Kocher, T., Murauer, E. M., Larcher, F., Del Rio, M., et al. (2017). COL7A1 editing via CRISPR/Cas9 in recessive dystrophic epidermolysis bullosa. Molecular Therapy : the Journal of the American Society of Gene Therapy., 25(11), 2573–2584.Google Scholar
  44. 44.
    Yu W, Mookherjee S, Chaitankar V, Hiriyanna S, Kim JW, Brooks M, et al. (2017) Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice. Nat Commun [Internet], 8, 1–15. Available from:  https://doi.org/10.1038/ncomms14716.
  45. 45.
    Pittenger, M. F., Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science., 284(5411), 143–147.Google Scholar
  46. 46.
    Lu, D. F., Yao, Y., Su, Z. Z., Zeng, Z. H., Xing, X. W., He, Z. Y., et al. (2014). Downregulation of HDAC1 is involved in the cardiomyocyte differentiation from mesenchymal stem cells in a myocardial microenvironment. PLoS One, 9(4), e93222.Google Scholar
  47. 47.
    Khanjani, S., Khanmohammadi, M., Zarnani, A. H., Talebi, S., Edalatkhah, H., Eghtesad, S., et al. (2015). Efficient generation of functional hepatocyte-like cells from menstrual blood-derived stem cells. Journal of Tissue Engineering and Regenerative Medicine., 9(11), E124–E134.Google Scholar
  48. 48.
    Lee, K. D., Kuo, T. K., Whang-Peng, J., Chung, Y. F., Lin, C. T., Chou, S. H., et al. (2004). In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology., 40(6), 1275–1284.Google Scholar
  49. 49.
    Zanini, C., Bruno, S., Mandili, G., Baci, D., Cerutti, F., Cenacchi, G., et al. (2011). Differentiation of mesenchymal stem cells derived from pancreatic islets and bone marrow into islet-like cell phenotype. PLoS One, 6(12), e28175.Google Scholar
  50. 50.
    Tohill, M., Mantovani, C., Wiberg, M., & Terenghi, G. (2004). Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration. Neuroscience Letters, 362(3), 200–203.Google Scholar
  51. 51.
    Tropel, P., Platet, N., Platel, J. C., Noel, D., Albrieux, M., Benabid, A. L., et al. (2006). Functional neuronal differentiation of bone marrow-derived mesenchymal stem cells. Stem Cells, 24(12), 2868–2876.Google Scholar
  52. 52.
    Di Rocco, G., Iachininoto, M. G., Tritarelli, A., Straino, S., Zacheo, A., Germani, A., et al. (2006). Myogenic potential of adipose-tissue-derived cells. Journal of cell science., 119(Pt 14), 2945–2952.Google Scholar
  53. 53.
    Goudenege, S., Pisani, D. F., Wdziekonski, B., Di Santo, J. P., Bagnis, C., Dani, C., et al. (2009). Enhancement of myogenic and muscle repair capacities of human adipose-derived stem cells with forced expression of MyoD. Molecular therapy : the Journal of the American Society of Gene Therapy., 17(6), 1064–1072.Google Scholar
  54. 54.
    Rajput, B. S., Chakrabarti, S. K., Dongare, V. S., Ramirez, C. M., & Deb, K. D. (2015). Human umbilical cord mesenchymal stem cells in the treatment of Duchenne muscular dystrophy: Safety and feasibility study in India. Journal of Stem Cells., 10(2), 141–156.Google Scholar
  55. 55.
    Hattori, H., Sato, M., Masuoka, K., Ishihara, M., Kikuchi, T., Matsui, T., et al. (2004). Osteogenic potential of human adipose tissue-derived stromal cells as an alternative stem cell source. Cells, Tissues, Organs., 178(1), 2–12.Google Scholar
  56. 56.
    Morrison, D. A., Kop, A. M., Nilasaroya, A., Sturm, M., Shaw, K., & Honeybul, S. (2018). Cranial reconstruction using allogeneic mesenchymal stromal cells: A phase 1 first-in-human trial. Journal of Tissue Engineering and Regenerative Medicine., 12(2), 341–348.Google Scholar
  57. 57.
    Thesleff, T., Lehtimaki, K., Niskakangas, T., Mannerstrom, B., Miettinen, S., Suuronen, R., et al. (2011). Cranioplasty with adipose-derived stem cells and biomaterial: A novel method for cranial reconstruction. Neurosurgery., 68(6), 1535–1540.Google Scholar
  58. 58.
    Bel, A., Planat-Bernard, V., Saito, A., Bonnevie, L., Bellamy, V., Sabbah, L., et al. (2010). Composite cell sheets: A further step toward safe and effective myocardial regeneration by cardiac progenitors derived from embryonic stem cells. Circulation., 122(11 Suppl), S118–S123.Google Scholar
  59. 59.
    Cai, M., Shen, R., Song, L., Lu, M., Wang, J., Zhao, S., et al. (2016). Bone marrow mesenchymal stem cells (BM-MSCs) improve heart function in swine myocardial infarction model through paracrine effects. Scientific Reports, 6, 28250.Google Scholar
  60. 60.
    Valina, C., Pinkernell, K., Song, Y. H., Bai, X., Sadat, S., Campeau, R. J., et al. (2007). Intracoronary administration of autologous adipose tissue-derived stem cells improves left ventricular function, perfusion, and remodelling after acute myocardial infarction. European Heart Journal., 28(21), 2667–2677.Google Scholar
  61. 61.
    Kholodenko, I. V., & Yarygin, K. N. (2017). Cellular mechanisms of liver regeneration and cell-based therapies of liver diseases. BioMed Research International., 2017, 8910821.Google Scholar
  62. 62.
    Liang, J., Zhang, H., Zhao, C., Wang, D., Ma, X., Zhao, S., et al. (2017). Effects of allogeneic mesenchymal stem cell transplantation in the treatment of liver cirrhosis caused by autoimmune diseases. International Journal of Rheumatic Diseases., 20(9), 1219–1226.Google Scholar
  63. 63.
    Zhang, Y., Li, Y., Zhang, L., Li, J., & Zhu, C. (2018). Mesenchymal stem cells: Potential application for the treatment of hepatic cirrhosis. Stem Cell Research & Therapy., 9(1), 59.Google Scholar
  64. 64.
    Kajiyama, H., Hamazaki, T. S., Tokuhara, M., Masui, S., Okabayashi, K., Ohnuma, K., et al. (2010). Pdx1-transfected adipose tissue-derived stem cells differentiate into insulin-producing cells in vivo and reduce hyperglycemia in diabetic mice. The International Journal of Developmental Biology., 54(4), 699–705.Google Scholar
  65. 65.
    Lin, G., Wang, G., Liu, G., Yang, L. J., Chang, L. J., Lue, T. F., et al. (2009). Treatment of type 1 diabetes with adipose tissue-derived stem cells expressing pancreatic duodenal homeobox 1. Stem Cells and Development., 18(10), 1399–1406.Google Scholar
  66. 66.
    Moreira, A., Kahlenberg, S., & Hornsby, P. (2017). Therapeutic potential of mesenchymal stem cells for diabetes. Journal of Molecular Endocrinology., 59(3), R109–RR20.Google Scholar
  67. 67.
    Okuda, A., Horii-Hayashi, N., Sasagawa, T., Shimizu, T., Shigematsu, H., Iwata, E., et al. (2017). Bone marrow stromal cell sheets may promote axonal regeneration and functional recovery with suppression of glial scar formation after spinal cord transection injury in rats. Journal of Neurosurgery SPINE., 26(3), 388–395.Google Scholar
  68. 68.
    Ryu, H. H., Lim, J. H., Byeon, Y. E., Park, J. R., Seo, M. S., Lee, Y. W., et al. (2009). Functional recovery and neural differentiation after transplantation of allogenic adipose-derived stem cells in a canine model of acute spinal cord injury. Journal of Veterinary Science., 10(4), 273–284.Google Scholar
  69. 69.
    Shende, P., & Subedi, M. (2017). Pathophysiology, mechanisms and applications of mesenchymal stem cells for the treatment of spinal cord injury. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie., 91, 693–706.Google Scholar
  70. 70.
    Ropper, A. E., Thakor, D. K., Han, I., Yu, D., Zeng, X., Anderson, J. E., et al. (2017). Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation. Proceedings of the National Academy of Sciences of the United States of America., 114(5), E820–E8E9.Google Scholar
  71. 71.
    Capitelli, C. S., Lopes, C. S., Alves, A. C., Barbiero, J., Oliveira, L. F., da Silva, V. J., et al. (2014). Opposite effects of bone marrow-derived cells transplantation in MPTP-rat model of Parkinson's disease: A comparison study of mononuclear and mesenchymal stem cells. International journal of medical sciences., 11(10), 1049–1064.Google Scholar
  72. 72.
    Jinfeng, L., Yunliang, W., Xinshan, L., Yutong, W., Shanshan, W., Peng, X., et al. (2016). Therapeutic effects of CUR-activated human umbilical cord mesenchymal stem cells on 1-Methyl-4-phenylpyridine-induced Parkinson's disease cell model. BioMed research international., 2016, 9140541.Google Scholar
  73. 73.
    Mendes Filho, D., Ribeiro, P. D. C., Oliveira, L. F., de Paula, D. R. M., Capuano, V., de Assuncao, T. S. F., et al. (2018). Therapy with mesenchymal stem cells in Parkinson disease: History and perspectives. The Neurologist., 23(4), 141–147.Google Scholar
  74. 74.
    Chulpanova, D. S., Kitaeva, K. V., Tazetdinova, L. G., James, V., Rizvanov, A. A., & Solovyeva, V. V. (2018). Application of mesenchymal stem cells for therapeutic agent delivery in anti-tumor treatment. Frontiers in Pharmacology., 9, 259.Google Scholar
  75. 75.
    Francois S, Usunier B, Forgue-Lafitte ME, L'Homme B, Benderitter M, Douay L, et al. (2018) Mesenchymal stem cell administration attenuates Colon Cancer progression by modulating the immune component within the colorectal tumor microenvironment. Stem cells translational medicine.Google Scholar
  76. 76.
    Kalimuthu, S., Zhu, L., Oh, J. M., Lee, H. W., Gangadaran, P., Rajendran, R. L., et al. (2018). Regulated mesenchymal stem cells mediated Colon Cancer therapy assessed by reporter gene based optical imaging. International journal of molecular sciences., 19(4).Google Scholar
  77. 77.
    Nakamura, K., Ito, Y., Kawano, Y., Kurozumi, K., Kobune, M., Tsuda, H., et al. (2004). Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Therapy., 11(14), 1155–1164.Google Scholar
  78. 78.
    Bartholomew, A., Sturgeon, C., Siatskas, M., Ferrer, K., McIntosh, K., Patil, S., et al. (2002). Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Experimental Hematology., 30(1), 42–48.Google Scholar
  79. 79.
    Ding, Q., Regan, S. N., Xia, Y., Oostrom, L. A., Cowan, C. A., & Musunuru, K. (2013). Enhanced efficiency of human pluripotent stem cell genome editing through replacing TALENs with CRISPRs. Cell Stem Cell, 12(4), 393–394.Google Scholar
  80. 80.
    Ding, Y., Li, H., Chen, L. L., & Xie, K. (2016). Recent advances in genome editing using CRISPR/Cas9. Frontiers in Plant Science, 7, 703.Google Scholar
  81. 81.
    Mali, P., Yang, L., Esvelt, K. M., Aach, J., Guell, M., DiCarlo, J. E., et al. (2013). RNA-guided human genome engineering via Cas9. Science., 339(6121), 823–826.Google Scholar
  82. 82.
    Barrero, M. J., Boue, S., & Izpisua Belmonte, J. C. (2010). Epigenetic mechanisms that regulate cell identity. Cell Stem Cell, 7(5), 565–570.Google Scholar
  83. 83.
    Chen, Q., Shou, P., Zheng, C., Jiang, M., Cao, G., Yang, Q., et al. (2016). Fate decision of mesenchymal stem cells: Adipocytes or osteoblasts? Cell Death and Differentiation., 23(7), 1128–1139.Google Scholar
  84. 84.
    Almalki, S. G., & Agrawal, D. K. (2016). Key transcription factors in the differentiation of mesenchymal stem cells. Differentiation; Research in Biological Diversity., 92(1–2), 41–51.Google Scholar
  85. 85.
    Augello, A., & De Bari, C. (2010). The regulation of differentiation in mesenchymal stem cells. Human Gene Therapy., 21(10), 1226–1238.Google Scholar
  86. 86.
    Bionaz, M., Monaco, E., & Wheeler, M. B. (2015). Transcription adaptation during in vitro Adipogenesis and osteogenesis of porcine mesenchymal stem cells: Dynamics of pathways, biological processes, up-stream regulators, and gene networks. PLoS One, 10(9), e0137644.Google Scholar
  87. 87.
    Kang, H., Minder, P., Park, M. A., Mesquitta, W. T., Torbett, B. E., & Slukvin, I. I. (2015). CCR5 disruption in induced pluripotent stem cells using CRISPR/Cas9 provides selective resistance of immune cells to CCR5-tropic HIV-1 virus. Molecular Therapy Nucleic Acids., 4, e268.Google Scholar
  88. 88.
    Lai, F. P., Lau, S. T., Wong, J. K., Gui, H., Wang, R. X., Zhou, T., et al. (2017). Correction of Hirschsprung-associated mutations in human induced pluripotent stem cells via clustered regularly interspaced short palindromic repeats/Cas9, restores neural crest cell function. Gastroenterology., 153(1), 139–53 e8.Google Scholar
  89. 89.
    Song, B., Fan, Y., He, W., Zhu, D., Niu, X., Wang, D., et al. (2015). Improved hematopoietic differentiation efficiency of gene-corrected beta-thalassemia induced pluripotent stem cells by CRISPR/Cas9 system. Stem Cells and Development., 24(9), 1053–1065.Google Scholar
  90. 90.
    Caplan, A. I., & Dennis, J. E. (2006). Mesenchymal stem cells as trophic mediators. Journal of Cellular Biochemistry, 98(5), 1076–1084.Google Scholar
  91. 91.
    Caplan, A. I., & Sorrell, J. M. (2015). The MSC curtain that stops the immune system. Immunology Letters., 168(2), 136–139.Google Scholar
  92. 92.
    Yao, Y., Huang, J., Geng, Y., Qian, H., Wang, F., Liu, X., et al. (2015). Paracrine action of mesenchymal stem cells revealed by single cell gene profiling in infarcted murine hearts. PLoS One, 10(6), e0129164.Google Scholar
  93. 93.
    Wu, C. C., Liu, F. L., Sytwu, H. K., Tsai, C. Y., & Chang, D. M. (2016). CD146+ mesenchymal stem cells display greater therapeutic potential than CD146- cells for treating collagen-induced arthritis in mice. Stem Cell Research & Therapy., 7, 23.Google Scholar
  94. 94.
    Butler, J., Epstein, S. E., Greene, S. J., Quyyumi, A. A., Sikora, S., Kim, R. J., et al. (2017). Intravenous allogeneic mesenchymal stem cells for nonischemic cardiomyopathy: Safety and efficacy results of a phase II-A randomized trial. Circulation Research., 120(2), 332–340.Google Scholar
  95. 95.
    Caplan, A. I., & Correa, D. (2011). The MSC: An injury drugstore. Cell Stem Cell, 9(1), 11–15.Google Scholar
  96. 96.
    Ye, X., Hu, J., & Cui, G. (2016). Therapy effects of bone marrow stromal cells on ischemic stroke. Oxidative medicine and cellular longevity., 2016, 7682960.Google Scholar
  97. 97.
    Yan, T., Chopp, M., & Chen, J. (2015). Experimental animal models and inflammatory cellular changes in cerebral ischemic and hemorrhagic stroke. Neuroscience Bulletin., 31(6), 717–734.Google Scholar
  98. 98.
    Diez-Tejedor, E., Gutierrez-Fernandez, M., Martinez-Sanchez, P., Rodriguez-Frutos, B., Ruiz-Ares, G., Lara, M. L., et al. (2014). Reparative therapy for acute ischemic stroke with allogeneic mesenchymal stem cells from adipose tissue: A safety assessment: A phase II randomized, double-blind, placebo-controlled, single-center, pilot clinical trial. Journal of Stroke and Cerebrovascular Diseases : the Official Journal of National Stroke Association., 23(10), 2694–2700.Google Scholar
  99. 99.
    Locatelli, F., Bersano, A., Ballabio, E., Lanfranconi, S., Papadimitriou, D., Strazzer, S., et al. (2009). Stem cell therapy in stroke. Cellular and Molecular Life Sciences : CMLS., 66(5), 757–772.Google Scholar
  100. 100.
    Zheng, H., Zhang, B., Chhatbar, P. Y., Dong, Y., Alawieh, A., Lowe, F., et al. (2018). Mesenchymal stem cell therapy in stroke: A systematic review of literature in pre-clinical and clinical research. Cell Transplantation., 27(12), 1723–1730.Google Scholar
  101. 101.
    Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V., & Ferrara, N. (1989). Vascular endothelial growth factor is a secreted angiogenic mitogen. Science., 246(4935), 1306–1309.Google Scholar
  102. 102.
    Conti, E., Carrozza, C., Capoluongo, E., Volpe, M., Crea, F., Zuppi, C., et al. (2004). Insulin-like growth factor-1 as a vascular protective factor. Circulation., 110(15), 2260–2265.Google Scholar
  103. 103.
    Abe, K., Yamashita, T., Takizawa, S., Kuroda, S., Kinouchi, H., & Kawahara, N. (2012). Stem cell therapy for cerebral ischemia: From basic science to clinical applications. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism., 32(7), 1317–1331.Google Scholar
  104. 104.
    Zhong, C., Qin, Z., Zhong, C. J., Wang, Y., & Shen, X. Y. (2003). Neuroprotective effects of bone marrow stromal cells on rat organotypic hippocampal slice culture model of cerebral ischemia. Neuroscience Letters, 342(1–2), 93–96.Google Scholar
  105. 105.
    Chiba, Y., Kuroda, S., Osanai, T., Shichinohe, H., Houkin, K., & Iwasaki, Y. (2012). Impact of ageing on biological features of bone marrow stromal cells (BMSC) in cell transplantation therapy for CNS disorders: Functional enhancement by granulocyte-colony stimulating factor (G-CSF). Neuropathology : official journal of the Japanese Society of Neuropathology., 32(2), 139–148.Google Scholar
  106. 106.
    Hokari, M., Kuroda, S., Chiba, Y., Maruichi, K., & Iwasaki, Y. (2009). Synergistic effects of granulocyte-colony stimulating factor on bone marrow stromal cell transplantation for mice cerebral infarct. Cytokine., 46(2), 260–266.Google Scholar
  107. 107.
    Kim, H. J., & Park, J. S. (2017). Usage of human mesenchymal stem cells in cell-based therapy: Advantages and disadvantages. Development & reproduction., 21(1), 1–10.Google Scholar
  108. 108.
    Kim, N., & Cho, S. G. (2015). New strategies for overcoming limitations of mesenchymal stem cell-based immune modulation. International Journal of Stem Cells., 8(1), 54–68.Google Scholar
  109. 109.
    Conboy, I., Murthy, N., Etienne, J., & Robinson, Z. (2018). Making gene editing a therapeutic reality. F1000Research., 7.Google Scholar
  110. 110.
    Wang, W., Huang, X., Lin, W., Qiu, Y., He, Y., Yu, J., et al. (2018). Hypoxic preconditioned bone mesenchymal stem cells ameliorate spinal cord injury in rats via improved survival and migration. International Journal of Molecular Medicine., 42(5), 2538–2550.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Daniel Mendes Filho
    • 1
  • Patrícia de Carvalho Ribeiro
    • 2
    • 3
  • Lucas Felipe Oliveira
    • 4
    • 5
    • 6
  • Ana Luiza Romero Terra dos Santos
    • 1
  • Ricardo Cambraia Parreira
    • 7
    Email author
  • Mauro Cunha Xavier Pinto
    • 7
  • Rodrigo Ribeiro Resende
    • 8
  1. 1.Department of Physiology, Ribeirao Preto Medical SchoolUniversity of Sao PauloRibeirao PretoBrazil
  2. 2.Laboratory of Immunology and Experimental TransplantationSão José do Rio Preto Medical SchoolSão José do Rio PretoBrazil
  3. 3.Division of Thoracic Surgery, Department of SurgeryMassachusetts General HospitalBostonUSA
  4. 4.Department of Physiology, Biological and Natural Sciences InstituteTriangulo Mineiro Federal UniversityUberabaBrazil
  5. 5.National Institute of Science and Technology for Regenerative Medicine (INCT-REGENERA-CNPq)Rio de JaneiroBrazil
  6. 6.Minas Gerais Network for Tissue Engineering and Cell Therapy (REMETTECFAPEMIG)Belo HorizonteBrazil
  7. 7.Department of Pharmacology, Biological Sciences InstituteGoias Federal UniversityGoianiaBrazil
  8. 8.Department of Biochemistry and ImmunologyFederal University of Minas GeraisBelo HorizonteBrazil

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