Abstract
Human cardiac progenitor cells (hCPC) are considered a good candidate in cell therapy for ischemic heart disease, demonstrating capacity to improve functional recovery after myocardial infarction (MI), both in small and large preclinical animal models. However, improvements are required in terms of cell engraftment and efficacy. Based on previously published reports, insulin-growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) have demonstrated substantial cardioprotective, repair and regeneration activities, so they are good candidates to be evaluated in large animal model of MI. We have validated porcine cardiac progenitor cells (pCPC) and lentiviral vectors to overexpress IGF-1 (co-expressing eGFP) and HGF (co-expressing mCherry). pCPC were transduced and IGF1-eGFPpos and HGF-mCherrypos populations were purified by cell sorting and further expanded. Overexpression of IGF-1 has a limited impact on pCPC expression profile, whereas results indicated that pCPC-HGF-mCherry cultures could be counter selecting high expresser cells. In addition, pCPC-IGF1-eGFP showed a higher cardiogenic response, evaluated in co-cultures with decellularized extracellular matrix, compared with native pCPC or pCPC-HGF-mCherry. In vivo intracoronary co-administration of pCPC-IGF1-eGFP and pCPC-HFG-mCherry (1:1; 40 × 106/animal), one week after the induction of an MI model in swine, revealed no significant improvement in cardiac function.
Highlights
The mammalian heart was believed to be a terminally differentiated organ in past decades, with no intrinsic capacity to regenerate after myocardial damage
Most of them show a reasonable comparative level of expression with the exception of GPR4 (−7.74 LogFC) and CDH5, CD9, and PTRF that are not expressed or at very low comparative levels in porcine cardiac progenitor cells (pCPC). We compared, both in two different isolates of pCPC and Human cardiac progenitor cells (hCPC), a selection of markers highly preferentially expressed in hCPC; IGFBP2 was used as a negative control being not expressed in hCPC [64]
All of them showed a compatible expression level in pCPC compared with hCPC IGF2R and CD9 were significantly overexpressed in human cells (Figure 2a)
Summary
The mammalian heart was believed to be a terminally differentiated organ in past decades, with no intrinsic capacity to regenerate after myocardial damage. In human and pig hearts, myocyte proliferation is a highly regulated process, as reviewed in Reference [2], that has been demonstrated in normal young human individuals (less than 20 years old) [3] and eventually potentiated in pathologic conditions, such as myocardial infarction (MI) [4] This suggests the existence of resident atypical progenitor cell population(s), from which new myocytes can be originated, as recently demonstrated in mammalian arteries for smooth muscle cells (SMC) [5]. Other cell surface markers were later proposed to describe resident subpopulations, including Sca-1, ATP-binding cassette (ABC) transporter ABCG2, or PDGFRα This diversity of potential markers, reviewed in Reference [7], has hindered unambiguous identification and molecular definition of endogenous cardiac stem/progenitor cells (CSC/CPC), in combination with several lineage-tracing analyses that yielded non-conclusive results [8,9]. Differentiation potential and function, both in homeostasis and in response to myocardial damage, CPC have been considered as an ideal candidate in cell therapy for ischemic heart disease [15]
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