Replacement of dead cardiomyocytes by scar tissue, unable to mediate normal cardiac
contraction, is the most dramatic change following heart infarction. Current dogma
investigates potential endogenous “self-repairing” capacity of the myocardium as a means to
minimize such degenerative process. Spontaneous regeneration of the myocardium could be
exploited to treat severe and frequently fatal conditions. Post ischaemic intrinsic cardiac
healing capability could arise because: i) Cardiomyocytes may proliferate and regenerate
damaged tissue, or; i) Endogenous cardiac stem cells (CSCs) may divide and differentiate to
exhibit cardiac repairing potential. Although CSCs existence has been documented, their
identity, intra-cardiac localization and exact potential remain elusive. Cardiac pericytes, which
ensheath blood vessels and express cardiac repair capabilities, could interact with c-kit+ CSCs
nested in vascular niches during cellular response to injury. I tested the hypothesis that
pericytes and endogenous cardiac progenitor’s stem cells might increase their interaction
within vascular niches under ischaemic conditions.
Focussing on the potential of cell therapies of cardiac disease, I investigated the spatial
relationship between pericytes and endogenous cardiac progenitors within stem cells' niches
localised in different regions of the human foetal, adult healthy and ischaemic heart.
Immunostaining of foetal human cardiac tissues showed that c-kit+ cells expression and their
association with pericytes decrease with heart development. Clear decrease is already evident
by 19th week of the gestation. Pericytes and c-kit+ cell populations isolated from foetal hearts
and expanded in culture reveal that pericytes’ cells express higher levels of the mesodermal
cardiac progenitor factor KDR: 3751± 61(SD) vs 398± 19.9 (SD); (P< 0.05) and for the marker
towards cardiac lineage Islet1: 1146±155 (SD) vs 728± 124 (SD); (P< 0.05) while c-kit+ cells
express higher levels than pericytes of the stemness marker SSEA3:1655± 40.6 (SD) vs 747±
27 (SD); (P< 0.05), known to progressively decrease with cell differentiation. Absence of
staining for CD31 marker in cultured cardiac pericytes and c-kit+ cells is replicated by results
of endothelial differentiation assessment, which shows that cardiac pericytes and c-kit+ cells
do not form CD31+ networks. The cardiac marker α-actin was present in both cell populations.
In healthy adult heart, pericytes marker CD146 localise within the vasculature. Following
ischaemia this pericyte marker becomes also evident outside the vasculature. In healthy adult
atrium, c-kit expression is low and coexpression with other markers inconspicuous. Ischaemia
leads to increased c-kit expression in the microvasculature. Furthermore, following ischaemia
c-kit, endothelium and pericyte markers colocalize within the same atrial cells. Colocalization
studies in ischaemic hearts revealed low levels of co-occurrence (M1/M2) between c-kit and
vascular markers in vessels <50μm but a high degree of correlation (PCC). Ischaemia leads to
increased c-kit expression, particularly in blood vessels <50um diameter. Blood
vessels >50μm diameter show mostly, staining for endothelial (vWF) and pericyte (CD146)
markers. Acute ischaemia of the left ventricle affected the detection of cardiac stem cells
markers in the infarcted area.
The absence of coexpression of markers during acute ischaemia of the left ventricle suggests
that post-ischaemia markers coexpresion is time dependent.
Conclusion: Foetal heart pericytes and c-kit+/CD117 cells express early cardiac
transcription factors and show trans-differentiation potential, which decreases in healthy adult
hearts. The preservation and activity of cardiac stem cells’ niches within the atrium
vasculature, appears re-activated in post-ischaemic hearts. Better understanding of cardiac c-kit+
and pericyte cells’ interactions during-human embryonic development and during
ischaemia may identify alternative novel therapeutic strategy against coronary artery disease