Improvement of cardiac function by placenta-derived mesenchymal stem cells does not require permanent engraftment and is independent of the insulin signaling pathway

Abstract

IntroductionThe objective of this work was to evaluate the efficacy of placenta-derived mesenchymal stem cell (MSC) therapy in a mouse model of myocardial infarction (MI). Since MSCs can be obtained from two different regions of the human term placenta (chorionic plate or villi), cells obtained from both these regions were compared so that the best candidate for cell therapy could be selected.MethodsFor the in vitro studies, chorionic plate MSCs (cp-MSCs) and chorionic villi MSCs (cv-MSCs) were extensively characterized for their genetic stability, clonogenic and differentiation potential, gene expression, and immunophenotype. For the in vivo studies, C57Bl/6 mice were submitted to MI and, after 21 days, received weekly intramyocardial injections of cp-MSCs for 3 weeks. Cells were also stably transduced with a viral construct expressing luciferase, under the control of the murine stem cell virus (MSCV) promoter, and were used in a bioluminescence assay. The expression of genes associated with the insulin signaling pathway was analyzed in the cardiac tissue from cp-MSCs and placebo groups.ResultsMorphology, differentiation, immunophenotype, and proliferation were quite similar between these cells. However, cp-MSCs had a greater clonogenic potential and higher expression of genes related to cell cycle progression and genome stability. Therefore, we considered that the chorionic plate was preferable to the chorionic villi for the isolation of MSCs. Sixty days after MI, cell-treated mice had a significant increase in ejection fraction and a reduction in end-systolic volume. This improvement was not caused by a reduction in infarct size. In addition, tracking of cp-MSCs transduced with luciferase revealed that cells remained in the heart for 4 days after the first injection but that the survival period was reduced after the second and third injections. Quantitative reverse transcription-polymerase chain reaction revealed similar expression of genes involved in the insulin signaling pathway when comparing cell-treated and placebo groups.ConclusionsImprovement of cardiac function by cp-MSCs did not require permanent engraftment and was not mediated by the insulin signaling pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/scrt490) contains supplementary material, which is available to authorized users.

Towards the standardization of stem cell therapy studies for ischemic heart diseases: Bridging the gap between animal models and the clinical setting

“…The advantages and limitations of each stem cell with regard to the possible emergence of ethical concerns (symbolized by ¥), the invasiveness and collection (from + to ++++), the isolation procedure, the abundance (from + to ++++), expansion and proliferation rate, the transdifferentiation capacity, the paracrine effects or/and cardiomyogenic potential, the survival and engraftment capacity as well as the immunogenic, oncogenic or teratogenic risks is given in the accessory side tables. The left table abridges bone marrow-derived stem cells [3,[19][20][21]27,28], cortical bone-derived stem cells [32,33], adipose tissue-derived stem cells [34,37,39,41] and gestation-related stem cells [42][43][44][45][46][47][48][49]51,54] and the right table abridges cardiac stem cells [57,59,60], skeletal muscle stem cells [62,63,66] and induced pluripotent stem cells [67,[69][70][71]. The human body scheme was constructed with images sourced from Servier Medical Art (http://www.servier.com/ Powerpoint-image-bank) and Cientic website (http://www.cientic.com/).…”

“…Pregnancy byproducts represent an important source of stem cells which can be obtained from a plethora of sources, such as placenta [42][43][44], chorionic plate [45], amniotic fluid [46], umbilical cord [47,48] and its blood [48][49][50][51]. These immune-privileged materials offer several advantages (Fig.…”

“…These immune-privileged materials offer several advantages (Fig. 1), like their non-invasive, safe and ethically accepted collection, their large availability, as well as their higher expansion and proliferation abilities than any other adult stem cell [42][43][44][45]. Furthermore, unlike adult stem cells, pregnancy-associated stem cells are not primed by senescence or disease conditions, thus making them good candidates for regenerative medicine [42].…”

“…This would be particularly important for elder patients, whose stem cell quality is expected to reduce with age [12]. Similarly to the above stem cell groups, it is thought that these cells act mainly through paracrine activity, stimulating vascularization, cardiomyogenesis, and inhibiting inflammation, fibrosis and apoptosis [42][43][44][45]47,48,51]. Also related to gestation, MSCs obtained from fetal heart tissue (fC-MSC) and embryonic stem cells (ESC) have been proposed as alternative multipotent cells with the ability to differentiate into CMs, endothelial and smooth muscle cells.…”

“…the absence of signs of myocardial structural and functional recovery [15,34,44,45,62,71,75] or the manifestation of adverse outcomes, such as arrhythmia [36]. These can be surpassed mainly by one of three alternatives, namely by electing a different stem cell type, by refining a population of stem cells or by adjusting the cell dosage/number of administrations (Box 3, Fig.…”