Die Rolle endogener und intravenös verabreichter Knochenmarkszellen im linksventrikulären Remodeling nach Myokardinfarkt

The therapeutic potential of systemically or locally injected bone
marrow cells (BMC) or mesenchymal stem cells in myocardial
infarction (MI) is a very controversial issue. Using human
placental alkaline phosphatase (hPLAP) as a genetic marker for cell
tracking, we examined the therapeutic efficacy and the homing of
intravenously administered, hPLAP labeled cells in marker tolerant,
immunocompetent rats after induction of MI. The marker enzyme hPLAP
provides superb histological detection quality in paraffin and
plastic sections. The influx of bone marrow-derived cells during
tissue repair was monitored in wild-type inbred Fischer 344 rats
reconstituted with bone marrow from transgenic F344 rats expressing
hPLAP under the control of the ubiquitous R26 promoter. Four months
post-MI, we found that the mesenchymal cells in the scar tissue
were almost exclusively of local origin. Intravenous administration
of 1x107 BMC from hPLAP transgenic donors administered 1 week
post-MI profoundly reduced the infiltration of the infarction site
by bone marrow-derived cells, and also the infarction area. No
differentiation of endogenous nor exogenous BMCs was observed. To
examine the homing of intravenous hPLAP labeled BMC in MI we
established a background-free syngeneic model for long-term
histological cell tracking in the absence of immune-mediated
rejection of labeled cells in immunocompetent animals. Skin grafts
showed that neonatal exposure of wild-type F344 rats to hPLAP
transgenic F344 cells results in lifelong tolerance to hPLAP
expressing tissues and cells. Using this model of neonatally
tolerized marker tolerant rats, we showed that only very few hPLAP
labeled BMC injected intravenously one week post-MI homed to the
infarction site. Therefore, we hypothesize that the beneficial
effect of intravenous BMC on left ventricular remodeling after MI
is caused by systemic immunomodulation.