The modulation of cardiac progenitor cell function by hydrogel-dependent Notch1 activation

Abstract

Myocardial infarction is the leading cause of death worldwide and phase I clinical trials utilizing cardiac progenitor cells (CPCs) have shown promising outcomes. Notch1 signaling plays a critical role in cardiac development and in the survival, cardiogenic lineage commitment, and differentiation of cardiac stem/progenitor cells. In this study, we functionalized self-assembling peptide (SAP) hydrogels with a peptide mimic of the Notch1 ligand Jagged1 (RJ) to evaluate the therapeutic benefit of CPC delivery in the hydrogels in a rat model of myocardial infarction. The behavior of CPCs cultured in the 3D hydrogels in vitro including gene expression, proliferation, and growth factor production was evaluated. Interestingly, we observed Notch1 activation to be dependent on hydrogel polymer density/stiffness with synergistic increase in presence of RJ. Our results show that RJ mediated Notch1 activation depending on hydrogel concentration differentially regulated cardiogenic gene expression, proliferation, and growth factor production in CPCs in vitro. In rats subjected to experimental myocardial infarction, improvement in acute retention and cardiac function was observed following cell therapy in RJ hydrogels compared to unmodified or scrambled peptide containing hydrogels. This study demonstrates the potential therapeutic benefit of functionalizing SAP hydrogels with RJ for CPC based cardiac repair.

Insight on stem cell preconditioning and instructive biomaterials to enhance cell adhesion, retention, and engraftment for tissue repair

“…biological molecules, adhesion ligands, adjustable ligand densities, cytokines, and growth factors), screening of suitable biomaterials depending upon the intended application, and the precise design of natural and synthetic biomaterials may alleviate these shortcomings and enhance cell transplantation efficiency and the associated therapeutic benefits [292]. Moreover, smart biomaterials can be designed as cell vehicles that can extend the viability of transplanted cells in vivo, control the differentiation of those cells into particular lineages, and allow for the precise release of cells [34,[293][294][295].…”

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

“…After being administered, cells can be nearly gone as soon as 1 to 3 days after transplantation [44,45]. However, some authors reported signs of stem cell survival up to 1 week [8,16,60,100,104], 1 month [14,18,23,27,30,37,46,52,67,105] and, most strikingly, up to 1 year [26]. When retained cells are quantified, we find that less than 3% of the stem cells survive more than 4 weeks [59,70] and that percentage drops to levels below 1% when the assessment is made 16 weeks after transplantation [106].…”

“…1). Surprisingly, though, they often exhibit poor survival and engraftment [57][58][59], that is why paracrine activity, mainly pro-angiogenic, has been attributed as their main mechanism of action, rather than the anticipated cardiomyogenic activity [60,61].…”

“…That is the rationale behind the use of multiple strategies in stem cell therapy investigations [60,66,102,104]. For example, Uchinaka and colleagues [66] tested the therapeutic potential of osteopontin-derived SV peptide (SVVYGLR)-transfected SKS in a rat model of CMI.…”

“…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/).…”