Microenvironmental Regulation of Cardiac Regeneration
Intramyocardial microenvironment determines the fate of human resident cardiac progenitor cells. We have recently identified a population of human progenitor cells that are characterized by the expression of both the CD105 cell marker and GATA-4 transcription factor.
Microenvironmental factors which induce activation of Wnt signaling results in generation and expansion of cardiac progenitors (Aisagbonhi et al, 2011).
Neuregulin-1β induces embryonic stem cell cardiomyogenesis via ErbB3/ErbB2 receptors (Hao et al, 2014). Cardiac stem/progenitor cells express ERBB2 and ERBB3 receptors and their stimulation with neuregulin-1 prevents differentiation towards myofibroblasts, reducing cardiac remodeling after heart injury (Galindo et al., 2014).
Our study identified A2B adenosine receptors on cardiac stromal cells as potential targets for up-regulation of proangiogenic factors in the heart. (Ryzhov et al, 2012).
Microenvironmental factors which mediate activation of Wnt-, ERBB- and AR- dependent signaling pathways promote generation, expansion and cardiomyogenic differentiation of resident CD105+CD31-CD45- cardiac progenitors, thus contributing to the rejuvenation of heart tissue in patients with heart failure.
Other ongoing areas of investigation:
- The role of retinoids in regulation of cardiac injury and failure
- Regulation of monocyte and fibroblast biology by neuregulin/ErbB signaling.
Interactions Between Immune and Cardiac Cells During Heart Recovery After Ischemic Heart Injury
Myocardial infarction (MI) is characterized by a marked cellular inflammatory response. CD45pos immune cells rapidly infiltrate injured myocardium, their numbers peaking at day 5 after MI when they become almost as abundant as all CD45neg non-myocyte cells (endothelial cell, fibroblasts, myofibroblasts, smooth muscle cells etc) combined (Fig. 1).
Myeloid cells are the majority of infiltrating cells during acute inflammatory and early reparative phases, and contribute to both pro-inflammatory and anti-inflammatory reactions. Our laboratory is primarily interested in studying the role of myeloid cells in the activation of cardiac progenitor cells and microvascular endothelial cells. We are currently characterizing the role of immune cells in the development of specific phenotype of cardiac mesenchymal stem-like cells using in vitro co-culture of conditionally immortalized cardiac Sca-1posCD31neg cells and different subpopulations of myeloid cells, including Ly6Gpos neutrophils, Ly6Chigh and Ly6Clow/neg monocytes, F4/80pos macrophages and monocyte-derived dendritic cells, generated from bone marrow derived lineage negative hematopoietic progenitor cells (HPC). We also investigating the molecular mechanisms involved in effects of adenosine differentiated dendritic cells (ADDC) on proliferation and morphogenic activity of microvascular endothelial cells.
NRG-1/ERBB Signaling in Myeloid Cells
Neuregulins (NRGs) belong to the epidermal growth factor (EGF) superfamily of transmembrane growth factors and included four members: NRG-1, NRG-2, NRG-3, and NRG-4. Among all neuregulins, NRG-1 has been intensively studied due to its essential role in cardiac development and in regulation of the adult cardiovascular system adaptation to physiological and pathological stress. NRGs signal through neuregulin receptors which include ERBB2, ERBB3 and ERBB4. NRG-1 binds to ERBB3 or ERBB4, and induces homo- and- heterodimer formation with each other (ERBB3/4 heterodimer, ERBB4/4 homodimer) or with ERBB2 (ERBB3/2 or ERBB4/2 heterodimers). ERBB2 has no ligand binding ability; its involvement in NRG-1 signaling is dependent upon heterodimerization with ERBB3 or ERBB4. Dimerization followed by tyrosine phosphorylation results in subsequent activation of downstream intracellular mediators of signaling including PI3K/AKT, Src/FAK, extracellular-regulated kinase (ERK1/2), nitric oxide synthase and cardiac myosin light chain kinase (cMLCK) (Fig. 2).