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  • Periodic Reporting for period 1 - STEMCELLTRACK (Assessment of Global and Regional Cardiac Functional Improvements in a Murine Model of Myocardial Infarction following Stem Cell Treatments)


Project ID: 652986
Funded under: H2020-EU.1.3.2.

Periodic Reporting for period 1 - STEMCELLTRACK (Assessment of Global and Regional Cardiac Functional Improvements in a Murine Model of Myocardial Infarction following Stem Cell Treatments)

Reporting period: 2015-07-01 to 2017-06-30

Summary of the context and overall objectives of the project

Cardiac progenitor stem cell (CPC) therapy for myocardial infarction (MI) has been shown to elicit moderate beneficial effects. Research currently focuses on improving CPC administration, retention, and efficacy. The conducted project work achieved the development of Magnetic Resonance Imaging (MRI) and engineering tools to facilitate this research in normal mice.
Intra-cardiac injections of CPCs labeled with perflurocrown-ether (PFCE) nanoparticles (NPs) and with the highly efficient transfection agent FuGENE can be visualized and tracked for the first time with 19F MRI in mice for approximately 8 days. The primary mechanisms attributing cellular status and temporal signal changes have been investigated, and have been shown to include (among others) possible: a) CPC migration/dispersion, b) cell death, and c) macrophage infiltration and scavenging. Furthermore, the developed methodologies achieved in vivo cardiac 19F MRI of injected labeled CPCs by reducing imaging acquisition to a few minutes, providing evidence for their potential for possible translational work.
Parallel to these studies there was an independent design, synthesis, use, and evaluation of a polymeric scaffolds. Overall, we have shown that porous, medium-chain length poly-caprolactone/poly(3-hydroxyoctanoate) polymer blends have superior performance in terms of the seeding density, adhesion, and CPC viability/proliferation. The choice of this material underlines one of the important novelties of pursued work, given its elastomeric nature, mechanical properties, and its potential to be conjugated with vascular growth factors and peptides to further prolong cellular attachment, viability, and proliferation. Its structural advantages/morphological characteristics are tunable and allow maximization of the seeding density for faster detection and temporal follow-up using direct, 19F MRI/MRS in vivo for at least 9 days post-implantation, as documented in mice.
Through a personalized career development plan, the fellowship allowed training of the researcher in advanced cellular characterization, synthesis, labeling, and bio-imaging techniques, synergistically with trans-European mobility through two secondments, reinforcing his scientific and managerial qualities.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The proposed work was pursued in accordance to three set objectives, including: a) the development and validation of fast, quantitative 19F MRI protocols for assessment of injected PFCE-NP-labeled CPCs, their retention, migration, and tracking in normal mice in vivo, b) the synthesis of a novel biodegradable scaffold and its in vitro characterization, and assessment of CPC retention and proliferation in vitro and post-implantation in mice in vivo (sham, SC-treated scaffold cohorts). Scientific work was c) supplemented and complemented with the development of complementary and new scientific skills, the accumulation of personal development skills through skilling and re-skilling, thereby allowing the applicant to reach a position of professional maturity in research.

Overall, from a scientific perspective, expended efforts have:

a) Achieved cardiac 19F-MRI of perfluoro-crown-ether (PFCE) labeled cardiac progenitor stem cells (CPCs) and bone-derived bone marrow macrophages
b) Determined label concentration and cellular load limits
c) Achieved spectroscopic and image-based quantification in vitro/post-mortem
d) Maximized the labeling efficiency and the 19F MRI detectability of CPCs using PFCE-NPs
e) Determined the temporal dynamics of single-cell label uptake
f) Quantified the temporal viability/fluorescence persistence of labeled CPCs in vitro
g) Implemented an in vivo, murine cardiac CPC administration protocol, MRI and tracking, that could be translatable to human applications
h) Achieved controlled delivery of CPCs on polymeric scaffolds, thereby prolonging the viability, and maximizing retention of delivered SCs to the murine myocardium
i) Extended the temporal window over which the release of labelled CPCs is achieved compared to traditional direct injection techniques, and
j) Used developed 19F MRI/MRS methodologies to noninvasively detect, and monitor the cells temporally over periods of 9 days post-implantation

On the forefront of training, collective efforts have allowed the fellow to acquire advanced knowledge and skilling/reskilling, through,

k) Attendance to two local conferences on SCs, two workshops, and three conferences
l) Completion of an animal training course
m) Attendance to an IP/Patents workshop
n) Attendance to grant/fellowship writing lectures/workshop
o) Completion of 10 professional/educational courses within U. Oxford
p) Two secondments (including trans-European mobility)

thereby allowing him to advance towards professional research/academic maturity.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The anticipated impact is expected to be multifaceted. Completed research work has contributed towards the advancement of scientific knowledge beyond the state-of-the-art, including the development of ultrafast image acquisition protocols for CPCs, labeling schemes that can now attain for the first time in vivo cardiac 19F MRI and tracking in the mouse, and the synthesis/use of polymeric scaffolds to visualize and allow controlled release of CPCs over prolonged time periods.
Future work is expected to further contribute towards the study of cardiac function in disease, and the potential applicability of generated results with cutting edge SC regenerative technologies in heart failure and prominent cardiomyopathies.
Expected European Socio-Economic Benefits: This proposal has directly addressed EU’s specific activities, including: a) the development of regenerative medicine and adapted treatments, and has provided evidence for the b) potential for transfer of knowledge to clinical practice. Critical to addressing structural EU problem drivers (enhancing contribution of research to tacking societal challenges, strengthening the science base, stimulating cross-border coordination), the MSCA objectives to enhance innovation and entrepreneurial skills, upgrade researcher skills and contribute to flagship initiative ‘Innovation Union’, ‘Youth on the Move’, and ‘Agenda for New Skills and Jobs’, were expended efforts to enhance working positions (potential to individuals, new career perspectives, strengthening of European capacity, contribution to structural and stage level education at European levels).
Benefit of the mobility to the European Research Area: Through secondments, this work has allowed enhancement of collaboration, acquisition of new skills and knowledge that in turn contribute to increased creativity, efficacy and performance, thereby contributing to career development and a successful, competitive knowledge-based society. The technical research and broader mobility and societal goals are envisaged to be enhanced further in the future, within the context of the analysis of cardiac functional effects of stem cell implantations on animal physiology and myocardial contraction and relaxation, the study of global/regional mechanical function, and the direct use of developed techniques in the study of mice with MI.

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