Frontières du vivant

Background
Cardiac-committed cells and biomimetic scaffolds independently improve the therapeutic efficacy of stem cells. This study tested the long-term effects of their combination.

Methods and Results
Eighty immune-deficient rats underwent permanent coronary artery ligation. Five to 7 weeks thereafter, those with an echocardiographically-measured ejection fraction (EF) ≤55% were reoperated on and randomly allocated to receive a cell-free fibrin patch (n=25), a fibrin patch loaded with 700,000 human embryonic stem cell (ESC) pre-treated to promote early cardiac differentiation (SSEA1+ progenitors [n=30]) or to serve as sham-operated animals (n=25). Left ventricular function was assessed by echocardiography at baseline and every month thereafter until 4 months. Hearts were then processed for the assessment of fibrosis and angiogenesis and a 5-component heart failure score was constructed by integrating the absolute change in left ventricular end-systolic volume (LVESV) between 4 months and baseline, and the qPCR-based expression of natriuretic peptides A and B, myosin heavy chain 7 and periostin. All data were recorded and analyzed blindly. The cell-treated group consistently yielded better functional outcomes than the sham-operated group (p=0.002 for EF; p=0.01 for LVESV). Angiogenesis in the border zone was also significantly greater in the cell-fibrin group (p=0.006) which yielded the lowest heart failure score (p=0.04 vs sham). Engrafted progenitors were only detected shortly after transplantation; no grafted cells were identified after 4 months. There was no teratoma either.

Conclusion
A fibrin scaffold loaded with ESC-derived cardiac progenitors results in sustained improvement of contractility and attenuation of remodelling without sustained donor cell engraftment. A paracrine effect, possibly on innate reparative responses, is a possible mechanism for this enduring effect.

Tissue engineering aims at recapitulating permissive conditions that enable cells to collaborate and form functional tissues. Applications range from human tissue modeling for diagnostic purposes to therapeutic solutions in regenerative medicine and surgery. Across this spectrum, human stem cells are the active ingredient, expandable virtually indefinitely and with the propensity to generate new tissue. Engaging lineage-specific differentiation requires a precise concerto of key spatial and temporal factors, such as soluble molecules and growth factors, but also physical and mechanical stimuli. These stimuli compete to modulate distinct developmental signaling pathways and ultimately affect the differentiation efficiency. The heart is a chemo-mechano-electrical biological system that behaves as both a sensor and an actuator. It can transduce electrical inputs to generate mechanical contraction and electrical wave propagation. Such a complex organ arises from multipart developmental events that interact with one another to self-regulate. Here, we overview the main events of heart development and the role of mechanical forces in modifying the microenvironment of the progenitor cells. We analyze the cascades regulating cardiac gene activation to illustrate how mechanotransduction is already involved in the most popular protocols for stem cell differentiation (SCD) into cardiomyocytes. We then review how forces are transmitted to embryonic stem cells (ESC) by cell-substrate or cell-cell communications, and how biomaterials can be designed to mimic these interactions and help reproduce key features of the developmental milieu. Putting this back in a clinical perspective, many challenges needs to be overcome before biomaterials-based SCD protocols can be scaled up and marketed.

A novel hybrid phage carrying genes from prokaryotic M13 phage and eukaryotic adeno-associated viruses can be used as a tissue engineering material with gene delivery functions. The filamentous shape of the resulting hybrid phage easily forms nanofibrous matrices, which can support cellular growth in tissue culture conditions and deliver the target programmed gene information into the target cells.