The human heart has poor endogenous regeneration. If myocytes are lost due
to injury, the myocardium is unable to restore its myocyte content and instead
undergoes compensatory hypertrophy and remodeling. Cardiac tissue
engineering aims to recreate and provide functional myocardium that replaces
the injured myocardium. In this study, human engineered heart muscle (EHM)
from cardiomyogenically differentiated human embryonic stem cells was
generated. EHMs consisted of elongated, anisotropically organized
cardiomyocyte bundles and responded “physiologically” to increasing calcium
concentrations. To generate large myocardium capable of encompassing the
ventricles, a novel process to systematically upscale the dimensions of
engineered myocardium to a humanized Biological Ventricular Assisted Device
(hBioVAD) was introduced. The hBioVADs formed a “pouch-like” myocardium at
rabbit heart dimensions and were beating spontaneously. Further enhancement
by biomimetic pulsatile loading generated “more mature” myocardium.
Additional paracrine functionality was integrated by generating insulin-like
growth factor-1 (IGF-1) secreting fibroblasts for tissue engineering applications.
IGF-1 release induced higher levels of Akt phosphorylation and hypertrophy in
cardiomyocytes resulting in increased force generation of EHM. Finally,
feasibility of “paraBioVAD” (IGF-1 cell line and cardiomyocytes) implantation
was demonstrated in a healthy rat model. Histological observations
demonstrated engraftment on the heart and the presence of vascular structures.
In conclusion, a humanized “paraBioVAD” technology for mechanic and
paracrine heart support was developed. Future studies will assess its
therapeutic utility in heart failure
| Identifer | oai:union.ndltd.org:uni-goettingen.de/oai:ediss.uni-goettingen.de:11858/00-1735-0000-000D-F03B-7 |
| Date | 23 October 2012 |
| Creators | Soong, Poh Loong |
| Contributors | Zimmermann, Wolfram-Hubertus Prof. Dr. |
| Source Sets | Georg-August-Universität Göttingen |
| Language | English |
| Detected Language | English |
| Type | doctoralThesis |
| Format | application/pdf |
| Rights | http://creativecommons.org/licenses/by-nc-nd/3.0/ |
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