Lecture+14_Beaudin_2014

Gov nct00474461 l problems lineage tracing eorts have

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Unformatted text preview: acZ- ) cardiac progenitors Regeneration in the neonatal rodent heart Porello et al, Science 2011 l༆  Neonatal mouse heart (P1) regenerates! l༆  Similar to zebrafish – proliferation of pre- existing cardiomyocytes l༆  Capacity gone by 7 days l༆  Very different mechanism than observed in adult – l༆  Can we replicate this later in life?? Regeneration in the mammalian heart? Adult regeneration Hsieh et al, Nature Med, 2007 Lineage tracing “pulse chase” Normal aging does NOT involve renewal from progenitors Limited regeneration from non- cardiomyocyte progenitors upon injury Very different regenerative mechanisms from ZF and neonatal heart Endogenous cardiac progenitors? l༆  Ckit+ cells within the heart – most studied à༎  Isolated cKit+ cells can give rise to CM, EC, and SMC in culture à༎  Transplanted cKit+ cells give rise to CM in MI model à༎  Autologous cKit+ cells currently in clinical trial as adjunct treatment for coronary bypass (Clinicatrial.gov NCT00474461) l༆  Problems: à༎  Lineage tracing efforts have demonstrated limited contribution of ckit+ cells to cardiomyocytes after injury à༎  Mast cells present in the heart are also cKit+ à༎  Difficult to discern cell fusion from cells truly giving rise to CM Regeneration in the the human heart?? l༆  Even more difficult to ascertain than in rodents l༆  Most CM have polyploid nucleus, many binucleated cells l༆  Most studies have involved laborious cell counting, biochemical assessment of DNA content, extrapolation from cell cycle parameters l༆  Novel approaches needed!! Regeneration in the human heart l༆  Took advantage of 14C atmospheric pulse that occurred with nuclear testing during cold war l༆  “Dating” of cardiomyocytes by 14C levels allows for “pulse chase” conditions “After” “Before” Bergmann et al, Science, 2009 l༆  All CM samples born before 1955 have high...
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This document was uploaded on 03/28/2014.

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