Noncanonical Wnt11 signaling is sufficient to induce cardiomyogenic differentiation in unfractionated bone marrow mononuclear cells

Michael P. Flaherty, Ahmed Abdel-Latif, Qianhong Li, Greg Hunt, Smita Ranjan, Qinghu Ou, Xian Liang Tang, Robin K. Johnson, Roberto Bolli, Buddhadeb Dawn

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


Background-Despite the frequent clinical use of adult unfractionated bone marrow mononuclear cells (BMMNCs) for cardiac repair, whether these cells are capable of undergoing cardiomyogenic differentiation in vitro remains uncertain. In addition, the role of Wnt signaling in cardiomyogenic differentiation of adult cells is unclear. Methods and Results-Unfractionated BMMNCs were isolated from adult mice via Ficoll-Paque density-gradient centrifugation and cultured in the presence of Wnt3a or Wnt11. In control BMMNCs, Wnt11 was not expressed, whereas the expression of markers of pluripotency (Oct-4 and Nanog), as well as that of Wnt3a and β-catenin, decreased progressively during culture. Exposure to Wnt3a rescued β-catenin expression and markedly increased the expression of Oct-4 and Nanog, concomitant with increased cell proliferation and CD45 expression. In contrast, exposure to ectopically expressed noncanonical Wnt11 markedly decreased the expression of Oct-4 and Nanog and induced mRNA expression (quantitative real-time reverse-transcription polymerase chain reaction) of cardiac-specific genes (Nkx2.5, GATA-4, atrial natriuretic peptide, α-and β-myosin heavy chain, and cardiac troponin T) by day 3 with subsequent progression to a pattern characteristic of the cardiac fetal gene program. After 21 days, 27.6±0.6% and 29.6±1.4% of BMMNCs expressed the cardiac-specific antigens cardiac myosin heavy chain and cardiac troponin T, respectively (immunocytochemistry), indicating cardiomyogenic lineage commitment. Wnt11-induced cardiac-specific expression was completely abolished by the protein kinase C inhibitor bisindolylmaleimide I, partially abolished by the c-Jun-N-terminal kinase inhibitor SP600125, and attenuated by the Wnt inhibitor Dickkopf-1. Conclusions-In adult density-gradient separated BMMNCs, canonical Wnt3a promotes stemness, proliferation, and hematopoietic commitment, whereas noncanonical signaling via Wnt11 induces robust cardiomyogenic differentiation in a protein kinase C-and c-Jun-N-terminal kinase-dependent manner. (Circulation. 2008;117:2241-2252.)

Original languageEnglish
Pages (from-to)2241-2252
Number of pages12
Issue number17
StatePublished - Apr 29 2008


  • Bone marrow cells
  • C-Jun N-terminal kinase
  • Cell differentiation
  • Protein kinase C
  • Stem cells
  • Wnt-3a protein
  • Wnt11 protein

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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