Research Article: Brain Derived Neurotrophic Factor Contributes to the Cardiogenic Potential of Adult Resident Progenitor Cells in Failing Murine Heart

Date Published: March 23, 2015

Publisher: Public Library of Science

Author(s): Rasmita Samal, Sabine Ameling, Vishnu Dhople, Praveen Kumar Sappa, Kristin Wenzel, Uwe Völker, Stephan B. Felix, Elke Hammer, Stephanie Könemann, Yaoliang Tang.

http://doi.org/10.1371/journal.pone.0120360

Abstract

Resident cardiac progenitor cells show homing properties when injected into the injured but not to the healthy myocardium. The molecular background behind this difference in behavior needs to be studied to elucidate how adult progenitor cells can restore cardiac function of the damaged myocardium. Since the brain derived neurotrophic factor (BDNF) moderates cardioprotection in injured hearts, we focused on delineating its regulatory role in the damaged myocardium.

Comparative gene expression profiling of freshly isolated undifferentiated Sca-1 progenitor cells derived either from heart failure transgenic αMHC-CyclinT1/Gαq overexpressing mice or wildtype littermates revealed transcriptional variations. Bdnf expression was up regulated 5-fold during heart failure which was verified by qRT-PCR and confirmed at protein level. The migratory capacity of Sca-1 cells from transgenic hearts was improved by 15% in the presence of 25ng/ml BDNF. Furthermore, BDNF-mediated effects on Sca-1 cells were studied via pulsed Stable Isotope Labeling of Amino acids in Cell Culture (pSILAC) proteomics approach. After BDNF treatment significant differences between newly synthesized proteins in Sca-1 cells from control and transgenic hearts were observed for CDK1, SRRT, HDGF, and MAP2K3 which are known to regulate cell cycle, survival and differentiation. Moreover BDNF repressed the proliferation of Sca-1 cells from transgenic hearts.

Comparative profiling of resident Sca-1 cells revealed elevated BDNF levels in the failing heart. Exogenous BDNF (i) stimulated migration, which might improve the homing ability of Sca-1 cells derived from the failing heart and (ii) repressed the cell cycle progression suggesting its potency to ameliorate heart failure.

Partial Text

Despite various attempts to develop therapeutics for cardiac disorders, the prevalence of heart failure was not considerably reduced. Moreover, the number of patients with heart failure is still growing due to demographic changes and higher survival rate after acute myocardial infarction. Although enormous progress has been made in the field of cardiovascular research, heart transplantation remains the solitary cure for end-stage heart failure till today. However, lack of donor hearts, tissue rejection and the high costs of treatment are major limitations in meeting the increasing demand of patients and foster the search for new treatment options. Over the last decade cell-based therapies emerged as potential alternatives in this regard. Accumulating evidence shows that a subset of undifferentiated progenitor cell populations resides in the adult heart, which is capable of promoting regeneration of the damaged myocardium [1–3] and thus offers new options towards endogenous cardiac repair mechanisms.

The adult mammalian heart harbors a subpopulation of cardiac progenitor cells that are capable of restoring myocardial function after injury. Homing of stem cells to a heart lesion is one of the pre-requisites for inducing repair processes via stem cell transplantation. Oh et al. have previously reported that resident Sca-1 cells home to the damaged myocardium and differentiate in part into functional cardiomyocytes when injected into diseased animals but showed no effect in healthy animals [4]. Therefore, a better understanding of molecular events during disease is quite essential for designing effective treatment options. To our knowledge the present study is the first to analyze the molecular characteristics of adult resident Sca-1 positive progenitor cells derived from the failing heart.

Here we have generated a comprehensive overview of global molecular changes in adult Sca-1 cells underlying heart failure conditions. Our comparative microarray-based study provided insights into their endogenous behavior during heart failure and unraveled their potential characteristics. The results indicate that the cardiogenic potential of Sca-1 cells is enhanced during heart failure condition. In addition, we explored the functional implications of BDNF expression, which was found to be elevated in failing hearts. We further provided supporting evidence on the regulatory role of exogenous BDNF on migration, proliferation and survival of progenitor cells, which might offer a therapeutic option for treatment of heart failure. However, it remains to be investigated whether local delivery of BDNF will improve the functional role of Sca-1 progenitor cells inside the damaged myocardium. Further in vivo experiments are necessary to extend our knowledge on BDNF driven fate of adult Sca-1 cells in cardiac dysfunction.

 

Source:

http://doi.org/10.1371/journal.pone.0120360