Abstract
Abstract only
Rationale:
Stem cells are constantly exposed to biomechanical and biochemical signals when transplanted in a continuously beating cardiac environment for treatment. Here, we postulated that an
in vitro
miniaturized beating cardiac microenvironment can induce unique biomechanical stimuli to co-cultured MSCs that can influence therapeutic potential of the later. This project aimed (i) to pre-condition mesenchymal stem cells (MSCs) with continuous mechanobiological stimuli using a 3D cardiac tissue environment (ii) to intramyocardially inject pre-conditioned MSCs into mice heart with myocardial infarction (MI) for tissue repair.
Methods:
We fabricated an
in vitro
cardiac platform as shown in
Fig 1
, using an electro-conductive hydrogel and human iPSC-derived cardiac cells. Adipose MSCs were then injected to the beating hydrogel platform. After 7 days, activated (MB+) and non-activated MSCs (MB-) were isolated for
in vitro
and
in vivo
analysis.
Results:
The force generated by the constant beating of cardiomyocytes induced profound effects in on MSC behavior in the MB+ group. Several mechano-transduction factors (YAP1, TAZ), actin polymerization genes involved in cardiac muscle contractions (
ACTA2
,
CDC42, TNNT2
) and angiogenic genes were upregulated in MB+. RNA-seq analysis further confirmed these findings. 3 week study in mice with MI demonstrated significant increase in capillary density and reduction in infarct sizes in MB+ (n=6) compared to MB- group. Furthermore, the MB+ group showed significantly higher cardiac performance in echocardiography.
We can conclude MB-activated MSCs can have significant impact in future treatment strategies for patients with MI.