The neurogenic response of cardiac resident nestin(+) cells was associated with GAP43 upregulation and abrogated in a setting of type I diabetes.
BACKGROUND
Cardiac nestin(+) cells exhibit properties of a neural progenitor/stem cell population characterized by the de novo synthesis of neurofilament-M in response to ischemic injury and 6-hydroxydopamine administration. The induction of growth associated protein 43 (GAP43) was identified as an early event of neurogenesis. The present study tested the hypothesis that the de novo synthesis of neurofilament-M by nestin(+) cells was preceded by the transient upregulation of GAP43 during the acute phase of reparative fibrosis in the infarcted male rat heart. Secondly, a seminal feature of diabetes is impaired wound healing secondary to an inadequate neurogenic response. In this regard, an additional series of experiments tested the hypothesis that the neurogenic response of cardiac nestin(+) cells was attenuated in a setting of type I diabetes.


METHODS
The neurogenic response of cardiac nestin(+) cells was examined during the early phase of reparative fibrosis following permanent ligation of the left anterior descending coronary artery in the adult male rat heart. The experimental model of type I diabetes was created following a single injection of streptozotocin in adult male rats. The impact of a type I diabetic environment on the neurogenic response of cardiac nestin(+) cells was examined during myocardial infarction and following the administration of 6-hydroxydopamine.


RESULTS
During the early phase of scar formation/healing, the density of GAP43/nestin(+) fibres innervating the peri-infarct/infarct region was significantly increased, whereas neurofilament-M/nestin(+) fibres were absent. With ongoing scar formation/healing, a temporal decrease of GAP43/nestin(+) fibre density and a concomitant increase in the density of innervating neurofilament-M/nestin(+) fibres were observed. The neurogenic response of cardiac nestin(+) cells during scar formation/healing was inhibited following the superimposition of type I diabetes. The de novo synthesis of neurofilament-M by nestin(+) cells after 6-hydroxydopamine administration was likewise attenuated in the heart of type I diabetic rats whereas the density of GAP43/nestin(+) fibres remained elevated.


CONCLUSIONS
The transient upregulation of GAP43 apparently represents a transition event during the acquisition of a neuronal-like phenotype and a type I diabetic environment attenuated the neurogenic response of cardiac nestin(+) cells to ischemia and 6-hydroxydopamine.
Montreal Heart Institute, Research Center, 5000 Belanger Street East, Montreal, QC H1T 1C8, Canada. angelo.calderone@umontreal.ca.
Andreanne
A
Chabot
Marc-Andre
MA
Meus
Vanessa
V
Hertig
Natacha
N
Duquette
Angelino
A
Calderone
D000818:Animals; D002921:Cicatrix / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D019922:GAP-43 Protein / Q000378:metabolism*; D006321:Heart / Q000294:innervation*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology; D064231:Nestin / Q000378:metabolism*; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016900:Neurofilament Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015854:Up-Regulation; D014945:Wound Healing
D019922:GAP-43 Protein; C577486:Nes protein, rat; D064231:Nestin; D016900:Neurofilament Proteins; C061195:neurofilament protein M; D016627:Oxidopamine