The cardiac neural stem cell phenotype is compromised in streptozotocin‐induced diabetic cardiomyopathy

Abstract

Neural stem cells were identified in the rat heart and during scar formation and healing participated in sympathetic fiber sprouting and angiogenesis. In the setting of diabetes, impaired wound healing represents a typical pathological feature. These findings provided the impetus to test the hypothesis that experimental diabetes adversely influenced the phenotype of cardiac neural stem cells. Streptozotocin (STZ)-induced diabetic rats were associated with elevated plasma glucose levels, significant loss of body weight and left ventricular contractile dysfunction. In the heart of STZ-diabetic rats, the density of nestin immunoreactive processes emanating from cardiac neural stem cells were reduced. The latter finding was reaffirmed as nestin protein expression was significantly decreased in the heart of STZ-diabetic rats and associated with a concomitant reduction of nestin mRNA. Employing the TUNEL assay, the loss of nestin expression in STZ-diabetic rats was not attributed to widespread cardiac neural stem cell apoptosis. Insulin administration to STZ-diabetic rats with established hyperglycaemia led to a modest recovery of nestin protein expression in cardiac neural stem cells. By contrast, the administration of insulin immediately after STZ injection improved plasma glucose levels and significantly attenuated the loss of nestin protein expression. These data highlight the novel observation that nestin protein expression in cardiac neural stem cells was significantly reduced in STZ-induced type I diabetic rats. The aberrant cardiac neural stem cell phenotype may compromise their biological role and predispose the diabetic heart to maladaptive healing following ischemic injury.

Nestin+cells and healing the infarcted heart

“…The upregulation of nestin in adult ventricular fibroblasts could lead to excessive proliferation and contribute in part to reactive fibrosis (41,49). A seminal feature of diabetes is impaired wound healing, and El-Helou and colleagues (22) reported the loss of nestin protein and mRNA expression in cardiac neural progenitor/stem cells in rat models of type I and type II diabetes. In this context, it is tempting to speculate that nestin-depleted neural progenitor/stem cells may predispose the diabetic heart to an inadequate reparative fibrotic response following ischemic damage.…”

Nestin downregulation in rat vascular smooth muscle cells represents an early marker of vascular disease in experimental type I diabetes

“…Experimental type I diabetes was induced following a single injection of streptozotocin (60 mg/kg) in the jugular vein of adult male Sprague-Dawley rats (9–11 weeks old) [15,16]. Plasma glucose levels and left ventricular function were determined as previously described [16].…”

“…A recent study by Oikawa and colleagues demonstrated that nestin was expressed in vascular smooth muscle cells of the adult rat aorta [14]. Work from our lab detected a population of cardiac resident nestin-expressing cells that exhibited a neural progenitor/stem cell phenotype and downregulation of the intermediate filament protein was identified as an incipient pathophysiological event of type I diabetes [8,9,15,16]. Based on these observations, the present study tested the hypothesis that nestin expression in vascular smooth muscle cells (VSMCs) of the adult rat carotid artery and aorta was directly linked to proliferation and the intermediate filament protein was downregulated during the early stage of experimental type I diabetes attributed to hyperglycaemia.…”

Development, Maturation, and Transdifferentiation of Cardiac Sympathetic Nerves

“…45 We and others also found reduced NGF in diabetic hearts which might explain the cardiac sensory denervation and neuropathy reported in diabetic patients. 55,[57][58][59] …”