Транскрипционные факторы ‒ ключевые регуляторные биомолекулы, определяющие направление дифференцировки мезенхимальных стволовых клеток в соматические клетки органов и тканей

В статье рассматриваются механизмы дифференцировки мезенхимальных стволовых клеток в соматические клетки органов и тканей, лежащие в основе эмбриогенеза и естественных репаративных процессов в клетке и поддерживающие структурный и функциональный гомеостаз клеточного пула в разрезе целостного организма, что тем самым определяет судьбу индивидуальных клеток. Приводятся данные об адипогенной, остеогенной, хондрогенной, миогенной и эндотелиальной дифференцировках, приводящих к формированию в организме системных клеток мезодермального происхождения. Рассматривается также вопрос о том, каким образом осуществляется контроль каждого из видов диффереренцировки и участие в них разнообразных регуляторных биомолекул, транскрипционных факторов, цитокинов и химокинов, находящихся в постоянном cложном взаимодействии друг с другом и образующих в клетке интегральную регуляторную сеть. Обсуждается участие в процессах дифференцировки ряда траскрипционых факторов (Runx2, Sox9, PPARγ, MyoD, GATA4 и GATA6), экспрессия которых находится под постоянным химическим контролем в пределах регуляторной сети клетки.

1. Origin of bone marrow stromal mechanocytes in radiochimeras and heterotopic transplants / A. J. Friedenstein [et al.] // Exp. Hematol. – 1978. – Vol. 6, N 5. – P. 440–444.

2. Caplan, A. I. Mesenchymal stem cells: building blocks for molecular medicine in the 21st century / A. I. Caplan, S. P. Bruder // Trends Mol. Med. – 2001. – Vol. 7, N 6. – P. 259–264. https://doi.org/10.1016/S1471-4914(01)02016-0

3. Herzog, E. L. Plasticity of marrow-derived stem cells / E. L. Herzog, L. Chai, D. S. Krause // Blood. – 2003. – Vol. 102, N 10. – P. 3483–3493. https://doi.org/10.1182/blood-2003-05-1664

4. Prockop, D. J. Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms / D. J. Prockop // Mol. Ther. – 2009. – Vol. 17, N 6. – P. 939–946. https://doi.org/10.1038/mt.2009.62

5. Chen, S. L. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction / S.-L. Chen [et al.] // Am. J. Cardiol. – 2004. – Vol. 94, N 1. – P. 92–95. https://doi.org/10.1016/j.amjcard.2004.03.034

6. le Blanc, K. Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation / K. le Blanc, O. Ringden // Biol. Blood Marrow Transplant. – 2005. – Vol. 11, N 5. – P. 321–334. https://doi.org/10.1016/j.bbmt.2005.01.005

7. A perivascular origin for mesenchymal stem cells in multiple human organs / M. Crisan [et al.] // Cell Stem Cell. – 2008. – Vol. 3, N 3. – P. 301–313. https://doi.org/10.1016/j.stem.2008.07.003

8. Almalki, S. G. Key transcription factors in the differentiation of mesenchymal stem cells / S. G. Almalki, D. K. Agrawal // Differentiation. – 2016. – Vol. 92, N 1–2. – P. 41–51. https://doi.org/10.1016/j.diff.2016.02.005

9. Friedenstein, A. J. Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers / A. J. Friedenstein, R. K. Chailakhyan, U. V. Gerasimov // Cell Tissue Kinet. – 1987. – Vol. 20, N 3. – P. 263–272. https://doi.org/10.1111/j.1365-2184.1987.tb01309.x

10. Augello, A. The regulation of differentiation in mesenchymal stem cells / A. Augello, C. de Bari // Hum. Gene Ther. – 2010. – Vol. 21, N 10. – P. 1226–1238. https://doi.org/10.1089/hum.2010.173

11. Clonal heterogeneity in differentiation potential of immortalized human mesenchymal stem cells / T. Okamoto [et al.] // Biochem. Biophys. Res. Commun. – 2002. – Vol. 295, N 2. – P. 354–361. https://doi.org/10.1016/S0006-291X(02)00661-7

12. Delivery of the Sox9 gene promotes chondrogenic differentiation of human umbilical cord blood-derived mesenchymal stem cells in an in vitro model / Z. H. Wang [et al.] // Braz. J. Med. Biol. Res. – 2014. – Vol. 47, N 4. – P. 279–286. https://doi.org/10.1590/1414-431X20133539

13. Chondrogenesis of human mesenchymal stem cells mediated by the combination of SOX trio SOX5, 6, and 9 genes complexed with PEI-modified PLGA nanoparticles / J. S. Park [et al.] // Biomaterials. – 2011. – Vol. 32, N 14. – P. 3679–3688. https://doi.org/10.1016/j.biomaterials.2011.01.063

14. Role of Hox genes in stem cell differentiation / A. Seifert [et al.] // World J. Stem Cells. – 2015. – Vol. 7, N 3. – P. 583–595. https://dx.doi.org/10.4252/wjsc.v7.i3.583

15. Yes-associated protein (YAP) is a negative regulator of chondrogenesis in mesenchymal stem cells / A. Karystinou [et al.] // Arthritis Res. Ther. – 2015. – Vol. 17, N 1. – P. 147. https://doi.org 10.1186/s13075-015-0639-9

16. Contribution of the interleukin-6/STAT-3 signaling pathway to chondrogenic differentiation of human mesenchymal stem cells / M. Kondo [et al.] // Arthritis Rheumatol. – 2015. – Vol. 67, N 5. – P. 1250–1260. https://doi.org.10.1002/art.39036

17. Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway / H. H. Zhang [et al.] // PLoS ONE. – 2009. – Vol. 4, N 7. – P. e6189. https://doi.org/10.1371/journal.pone.0006189

18. Molecular mechanisms of PPAR-gamma governing MSC osteogenic and adipogenic differentiation / H. Zhuang [et al.] // Curr. Stem Cell Res. Ther. – 2015. – Vol. 11, N 3. – P. 255–264. https://doi.org/10.2174/1574888x10666150531173309

19. Regulation of adipocyte differentiation of bone marrow stromal cells by transcription factor GATA-2 / Y. Okitsu [et al.] // Biochem. Biophys. Res. Commun. – 2007. – Vol. 364, N 2. – P. 383–387. https://doi.org/10.1016/j.bbrc.2007.10.031

20. TWIST family of basic helix-loop-helix transcription factors mediate human mesenchymal stem cell growth and commitment / S. Isenmann [et al.] // Stem Cells. – 2009. – Vol. 27, N 10. – P. 2457–2468. https://doi.org/10.1002/stem.181

21. MicroRNA-194 reciprocally stimulates osteogenesis and inhibits adipogenesis via regulating COUP-TFII expression / B. C. Jeong [et al.] // Cell Death Dis. – 2014. – Vol. 5, N 11. – P. e1532. https://doi.org/10.1038/cddis.2014.485

22. Adult mesenchymal stem cells: differentiation potential and therapeutic applications / L. Jackson [et al.] // Postgrad. Med. – 2007. – Vol. 53, N 2. – P. 121–127. https://doi.org/10.4103/0022-3859.32215

23. Charytonowicz, E. Alternate PAX3 and PAX7 C-terminal isoforms in myogenic differentiation and sarcomagenesis / E. Charytonowicz // Clin. Transl. Oncol. – 2011. – Vol. 13, N 3. – P. 194–203. https://doi.org/10.1007/s12094-011-0640-y

24. Pax3 activation promotes the differentiation of mesenchymal stem cells toward the myogenic lineage / E. J. Gang [et al.] // Exp. Cell Res. – 2008. – Vol. 314, N 8. – P. 1721–1733. https://doi.org/10.1016/j.yexcr.2008.02.016

25. MyoD transcription factor induces myogenesis by inhibiting Twist-1 through miR-206 / D. Koutalianos [et al.] // J. Cell Sci. – 2015. – Vol. 128, N 19. – P. 3631–3645. https://doi.org/10.1242/jcs.172288

26. TAZ as a novel enhancer of MyoD-mediated myogenic differentiation / H. Jeong [et al.] // FASEB J. – 2010. – Vol. 24, N 9. – P. 3310–3320. https://doi.org/10.1096/fj.09-151324

27. TNF alpha inhibits myogenic differentiation of C2C12 cells through NF-kappaB activation and impairment of IGF-1 signaling pathway/ Q. Zhao [et al.] // Biochem. Biophys. Res. Commun. – 2015. – Vol. 458, N 4. – P. 790–795. https://doi.org/10.1016/j.bbrc.2015.02.026

28. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation / K. E. Hatzistergos [et al.] // Circ. Res. – 2010. – Vol. 107, N 7. – P. 913–922. https://doi.org/10.1161/CIRCRESAHA.110.222703

29. Thioredoxin-1 (Trx1) engineered mesenchymal stem cell therapy increased pro-angiogenic factors, reduced fibrosis and improved heart function in the infarcted rat myocardium / S. C. Suresh [et al.] // Int. J. Cardiol. – 2015. – Vol. 201. – P. 517–528. https://doi.org/10.1016/j.ijcard.2015.08.117

30. Activation of Notch1 signalling promotes multi-lineage differentiation of c-Kit(POS)/NKX2.5(POS) bone marrow stem cells: implication in stem cell translational medicine / R. Ding [et al.] // Stem Cell Res. Ther. – 2015. – Vol. 6, N 1. – P. 91. https://doi.org/10.1186/s13287-015-0085-2

31. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing / G. Chamberlain [et al.] // Stem Cells. – 2007. – Vol. 25, N 11. – P. 2739–2749. https://doi.org/10.1634/stemcells.2007-0197

32. Sphingosine 1-phosphate induces differentiation of mesoangioblasts towards smooth muscle. A role for GATA6 / C. Donati [et al.] // PLoS ONE. – 2011. – Vol. 6, N 5. – P. e20389. https://doi.org/10.1371/journal.pone.0020389

33. Peroxisome proliferator-activated receptor gamma negatively regulates the differentiation of bone marrow-derived mesenchymal stem cells toward myofibroblasts in liver fibrogenesis / S. Jia [et al.] // Cell Physiol. Biochem. – 2015. – Vol. 37, N 6. – P. 2085–2100. https://doi.org/10.1159/000438567

34. Mesenchymal stromal cells for sphincter regeneration: role of laminin isoforms upon myogenic differentiation / T. Seeger [et al.] // PLoS ONE. – 2015. – Vol. 10, N 9. – P. e0137419. https://doi.org/10.1371/journal.pone.0137419

35. Shi, N. From nerve to blood vessel: a new role of Olfm2 in smooth muscle differentiation from human embryonic stem cell-derived mesenchymal cells / N. Shi, S. Y. Chen // J. Biomed. Res. – 2015. – Vol. 29, N 4. – P. 261–263. https://doi.org/10.7555/JBR.29.20150027

36. Pankajakshan, D. In vitro differentiation of bone marrow derived porcine mesenchymal stem cells to endothelial cells / D. Pankajakshan, V. Kansal, D. K. Agrawal // J. Tissue Eng. Regen. Med. – 2013. – Vol 7, N 11. – P. 911–920. https://doi.org/10.1002/term.1483

37. Ikhapoh, I. A. Synergistic effect of angiotensin II on vascular endothelial growth factor-A-mediated differentiation of bone marrow-derived mesenchymal stem cells into endothelial cells / I. A. Ikhapoh, C. J. Pelham, D. K. Agrawal // Stem Cell Res. Ther. – 2015. – Vol. 6, N 1. – P. 4. https://doi.org/10.1186/scrt538