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Title page for ETD etd-03272017-212556


Type of Document Dissertation
Author Bylund, Jeffery B.
URN etd-03272017-212556
Title BMP signaling regulation by GREMLIN 2 promotes proliferation and differentiation of human iPS cell-derived cardiac progenitors to cardiomyocytes
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Joey V. Barnett Committee Chair
Aaron B. Bowman Committee Member
Antonis K. Hatzopoulos Committee Member
Christopher B. Brown Committee Member
H. Scott Baldwin Committee Member
Keywords
  • cardiomyocyte differentiation
  • human pluripotent stem cells
  • BMP signaling
  • GREMLIN 2
Date of Defense 2017-03-02
Availability unrestricted
Abstract
Heart development depends on coordinated proliferation and differentiation of cardiac progenitor cells, but how the two processes are synchronized is not well understood. The data herein show that the secreted BMP antagonist GREMLIN 2 (GREM2) is induced in cardiac progenitor cells shortly after cardiac mesoderm specification during differentiation of human pluripotent stem cells. GREM2 expression follows cardiac lineage differentiation independently of the differentiation method used, or the origin of the pluripotent stem cells, suggesting that GREM2 is linked to cardiogenesis. Addition of GREM2 protein strongly increases cardiomyocyte output compared to established pro-cardiogenic differentiation methods. These data show that inhibition of canonical BMP signaling by GREM2 is necessary to promote proliferation of cardiac progenitor cells. However, canonical BMP signaling inhibition alone is not sufficient to induce cardiac differentiation, which depends on subsequent JNK pathway activation specifically by GREM2. These findings may have broader implications in the design of approaches to orchestrate growth and differentiation of pluripotent stem cell-derived lineages that depend on precise regulation of BMP signaling.
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