Changes of angiogenic properties of adipose derived MMSC in patients with coronary heart disease with age

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access


Tissue regeneration is impaired in aged individuals. Adipose- derived multipotent mesenchymal stromal cells (adMMSC), a promising source for cell therapy, were shown to secrete various angiogenic factors and improve vascularization of ischemic tissues. We analyzed how patient age affected angiogenic properties of adMMSC. adMMSC were isolated from surgically obtained subcutaneous fat tissue of patients (n = 64, 43-77 years old) with coronary artery disease (CAD). adMMSC phenotype characterized by flow cytometry was CD90+/ CD73+/CD105+/CD45-/CD31- for all samples and cells were capable for adipogenic and osteogenic differentiation. adMMSC conditioned media stimulated formation of capillary-like tubes by endothelial cells (EA.hy926) and this effect significantly decreased with age of patients. There was no age-associated difference in angiogenic factors gene expression (evaluated by real-time PCR). Level of pro- angiogenic factors in adMMSC conditioned media measured by ELISA significantly declined with age of patients, but level of anti-angiogenic factors did not. Thus, angiogenic properties of adMMSC from aged patients with CAD decline due to the decreasing of pro- angiogenic factors secretion. Our data provide new insights into mechanisms of age-associated impairment of autologous adMMSC therapeutic potential.

Full Text

Restricted Access

About the authors

A. Y Efimenko

M.V. Lomonosov Moscow State University, Moscow

N. A Dgoyashvili

M.V. Lomonosov Moscow State University, Moscow

N. I Kalinina

M.V. Lomonosov Moscow State University, Moscow

T. N Kochegura

M.V. Lomonosov Moscow State University, Moscow

R. S Achkurin

Russian Cardiology Research and Production Complex of the Ministry of Health, Moscow

V. A Tkachuk

M.V. Lomonosov Moscow State University, Moscow; Russian Cardiology Research and Production Complex of the Ministry of Health, Moscow

E. V Parfenova

M.V. Lomonosov Moscow State University, Moscow; Russian Cardiology Research and Production Complex of the Ministry of Health, Moscow


  1. Gimble J.M., Bunnell B.A., Chiu E.S. et al. Concise review: adipose derived stromal vascular fraction cells and stem cells: let's not get lost in translation. Stem Cells 2011; 29(5): 749—54.
  2. Strem B.M., Hicok K.C., Zhu M. et al. Multipotential differentiation of adipose tissue-derived stem cells. Keio J. Med. 2005; 54: 132-41.
  3. Парфенова Е.В., Цоколаева З.И., Трактуев Д.О. и др. Поиск новых «инструментов» для терапевтического ангиогенеза. Молекулярная медицина 2006; 2: 10-23.
  4. Трактуев Д.О., Марч К.Л., Ткачук В.А. и др. Стромальные клетки жировой ткани — мультипотентные клетки с терапевтическим потенциалом для стимуляции ангиогенеза при ишемии тканей. Кардиология 2006; 46(6): 53—63.
  5. Трактуев Д.О., Парфенова Е.В., Ткачук В.А. и др. Стромальные клетки жировой ткани — пластический тип клеток с высоким терапевтическим потенциалом. Цитология 2006; 48(2): 83—94.
  6. Rehman J., Traktuev D., Li J. et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 2004; 109: 1292—8.
  7. Miyahara Y., Nagaya N., Kataoka M. et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat. Med. 2006; 12: 459—65.
  8. Nakagami H., Morishita R., Maeda K. et al. Adipose tissue- derived stromal cells as a novel option for regenerative cell therapy. J. Atheroscler. Thromb. 2006; 13: 77—81.
  9. Gimble J. M., Katz A. J., Bunnell B. A. Adipose-derived stem cells for regenerative medicine. Circ. Res. 2007; 100: 1249—60.
  10. Zhang D.Z., Gai L.Y., Liu H.W. et al. Transplantation of autologous adipose-derived stem cells ameliorates cardiac function in rabbits with myocardial infarction. Chin. Med. J. (Engl). 2007; 120: 300—7.
  11. Cai L., Johnstone B.H., Cook T.G. et al. IFATS collection: human adipose tissue-derived stem cells induce angiogenesis and nerve sprouting following myocardial infarction, in conjunction with potent preservation of cardiac function. Stem Cells 2009; 27: 230—7.
  12. Kondo K., Shintani S., Shibata R. et al. Implantation of adipose- derived regenerative cells enhances ischemia-induced angiogenesis. Arterioscler. Thromb. Vasc. Biol. 2009; 29: 61—6.
  13. Rubina K., Kalinina N., Efimenko A. et al. Adipose stromal cells stimulate angiogenesis via promoting progenitor cell differentiation, secretion of angiogenic factors, and enhancing vessel maturation. Tissue Eng. Part A. 2009; 15: 2039—50.
  14. Madonna R., De Caterina R. Adipose tissue: a new source for cardiovascular repair. J. Cardiovasc. Med. (Hagerstown). 2010; 11: 71—80.
  15. Kachgal S., Putnam A.J. Mesenchymal stem cells from adipose and bone marrow promote angiogenesis via distinct cytokine and protease expression mechanisms. Angiogenesis 2011; 14(1): 47—59.
  16. Miranville A., Heeschen C., Sengenes C. et al. Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation 2004; 110: 349—55.
  17. Planat-Benard V., Silvestre J. S., Cousin B. et al. Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation 2004; 109: 656—63.
  18. Sumi M., Sata M., Toya N. et al. Transplantation of adipose stromal cells, but not mature adipocytes, augments ischemia-induced angiogenesis. Life Sci. 2007; 80: 559—65.
  19. Nombela-Arrieta C., Ritz J., Silberstein L.E. The elusive nature and function of mesenchymal stem cells. Nat. Rev. Mol. Cell Biol. 2011; 12(2): 126—31.
  20. Madonna R., Geng Y.J., De Caterina R. Adipose tissue-derived stem cells: characterisation and potencial for cardiovascular repair. Arterioscler. Thromb. Vasc. Biol. 2009; 29: 1723—729.
  21. Murohara T., Shintani S., Kondo K. Autologous adipose- derived regenerative cells for therapeutic angiogenesis. Curr. Pharm. Des. 2009; 15(24): 2784—90.
  22. Bailey A.M., Kapur S., Katz A. J. Characterization of adipose- derived stem cells: an update. Curr. Stem Cell. Res. Ther. 2010; 5(2): 95—102.
  23. Fehrer C., Lepperdinger G. Mesenchymal stem cell aging. Exp. Gerontol. 2005; 40: 926—30.
  24. Sethe S., Scutt A., Stolzing A. Aging of mesenchymal stem cells. Ageing Res. Rev. 2006; 5: 91—116.
  25. Stolzing A., Sethe S., Scutt A. M. Stressed stem cells: Temperature response in aged mesenchymal stem cells. Stem Cells Dev. 2006; 15: 478—87.
  26. Katsara O., Mahaira L.G., Iliopoulou E.G. et al. Effects of donor age, gender and in vitro cellular aging on the phenotype, functional and molecular characteristics of mouse bone marrow-derived mesenchymal stem cells. Stem Cells Dev. 2011; 20(9): 1549—61.
  27. Sun Y., Li W., Lu Z. et al. Rescuing replication and osteogenesis of aged mesenchymal stem cells by exposure to a young extracellular matrix. FASEB 2011; 25(5): 1474—85.
  28. Zhu M., Kohan E., Bradley J. et al. The effect of age on osteogenic, adipogenic and proliferative potential of female adipose- derived stem cells. J. Tissue Eng. Regen. Med. 2009; 3: 290—301.
  29. Huang S.C., Wu T.C., Yu H.C. et al. Mechanical strain modulates age-related changes in the proliferation and differentiation of mouse adipose-derived stromal cells. BMC Cell Biology 2010; 11: 18.
  30. El-Ftesi S., Chang E.I., Longaker M.T. et al. Aging and diabetes impair the neovascular potential of adipose-derived stromal cells. Plast. Reconstr. Surg. 2009; 123: 475—85.
  31. Zuk P.A., Zhu M., Ashjian P. et al. Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell. 2002; 13: 4279—95.
  32. Aranda E., Owen G.I. A semi-quantitative assay to screen for angiogenic compounds and compounds with angiogenic potential using the EA.hy926 endothelial cell line. Biol. Res. 2009; 42(3): 377—89.
  33. Dominici M., Le Blanc K., Mueller I., et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4): 315—7.
  34. Flores I., Blasco M. A. The role of telomeres and telomerase in stem cell aging. FEBS Lett. 2010; 584: 3826—30.
  35. Dasgupta J., Kar S., Liu R. et al. Reactive oxygen species control senescence-associated matrix metalloproteinase-1 through c-Jun-N-terminal kinase. J. Cell Physiol. 2010; 225: 52—62.
  36. Baxter M.A., Wynn R.F., Jowitt S.N. et al. Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. Stem Cells 2004; 22: 675—82.
  37. Stolzing A., Jones E., McGonagle D., Scutt A. Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech. Ageing Dev. 2008; 129: 163—73.
  38. Wilson A., Shehadeh L.A., Yu H. et al. Age-related molecular genetic changes of murine bone marrow mesenchymal stem cells. BMC Genomics 2010; 11: 229.
  39. de Girolamo L., Lopa S., Arrigoni E. et al. Human adipose- derived stem cells isolated from young and elderly women: their differentiation potential and scaffold interaction during in vitro osteoblastic differentiation. Cytotherapy 2009; 11(6): 793—803.
  40. Harris L.J., Zhang P., Abdollahi H. et al. Availability of adipose- derived stem cells in patients undergoing vascular surgical procedures. J. Surg. Res. 2010; 163(2): e105—12.
  41. van Harmelen V., Skurk T., Hauner H. Primary culture and differentiation of human adipocyte precursor cells. Methods Mol. Med. 2005; 107: 125—35.
  42. Schipper B.M., Marra K.G., Zhang W. et al. Regional anatomic and age effects on cell function of human adipose-derived stem cells. Ann. Plast. Surg. 2008; 60: 538—44.
  43. Khan W.S., Adesida A.B., Tew S.R. et al. The epitope characterisation and the osteogenic differentiation potential of human fat pad-derived stem cells is maintained with ageing in later life. Injury 2009; 40: 150—7.
  44. Efimenko A.Yu., Starostina E.E., Kalinina N.I. et al. Angiogenic properties of aged adipose derived mesenchymal stem cells after hypoxic conditioning. Translat. Med. 2011; 9: 10.
  45. Ефименко А.Ю., Старостина Е.Е., Калинина Н.И. и др. Влияние возраста на ангиогенные свойства мезенхимальных стволовых клеток жировой ткани. Клеточная трансплантология и тканевая инженерия 2011; VI(3): 48-57.
  46. Sadat S., Gehmert S., Song Y. H. et al. The cardioprotective effect of mesenchymal stem cells is mediated by IGF-I and VEGF. Biochem. Biophys. Res. Commun. 2007; 363(3): 674-9.
  47. Cai L., Johnstone B. H., Cook T. G. et al. Suppression of hepatocyte growth factor production impairs the ability of adipose- derived stem cells to promote ischemic tissue revascularization. Stem Cells 2007; 25(12): 3234-43.
  48. Jiang S., Kh Haider H., Ahmed R.P. et al. Transcriptional profiling of young and old mesenchymal stem cells in response to oxygen deprivation and reparability of the infarcted myocardium. J. Mol. Cell Cardiol. 2008; 44: 582-96.
  49. Sadoun E., Reed M.J. Impaired angiogenesis in aging is associated with alterations in vessel density, matrix composition, inflammatory response, and growth factor expression. J. Histochem. Cytochem. 2003; 51: 1119-30.
  50. Gao X., Xu Z. Mechanisms of action of angiogenin. Acta Biochim. Biophys. Sin. 2008; 40(7): 619-24.
  51. Jimi S., Ito K., Kohno K. et al. Modulation by bovine angiogenin of tubular morphogenesis and expression of plasminogen activator in bovine endothelial cells. Biochem. Biophys. Res. Commun. 1995; 211(2): 476-83.
  52. Distler J.W., Hirth A., Kurowska-Stolarska M. Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q. J. Nucl. Med. 2003; 47: 149-61.
  53. Reiss Y. Angiopoietins. Recent. Results Cancer Res. 2010; 180: 3-13.
  54. Thurston G., Suri C., Smith K. et al. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 1999; 286: 2511-14.
  55. Chae J.K., Kim I., Lim S.T. et al. Coadministration of angiopoietin-1 and vascular endothelial growth factor enhances collateral vascularization. Arterioscl. Thromb. Vasc. Biol. 2000; 20: 2573-8.
  56. Song N., Ding Y., Zhuo W. et al. The nuclear translocation of endostatin is mediated by its receptor nucleolin in endothelial cells. Angiogenesis 2012; 15(4): 697-711.
  57. Lawler PR, Lawler J. Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harb. Perspect. Med. 2012; 2(5): a006627.
  58. Olson B.A., Day J.R., Laping N.J. Age-related expression of renal thrombospondin 1 mRNA in F344 rats: resemblance to diabetes- induced expression in obese Zucker rats. Pharmacology 1999; 58: 200-8.
  59. Шевченко Е.К., Макаревич П.И., Цоколаева З.И. и др. Эффективная трансдукция стромальных клеток жировой ткани человека с помощью рекомбинантного аденоассоциированного вируса. Клеточная трансплантология и тканевая инженерия 2010; V(1): 60-64.

Copyright (c) 2012 Eco-Vector

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ПИ № ФС 77 - 85657 от 21.07.2023 от 11.03.2014.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies