5^th International Conference on Tissue Engineering and Regenerative Medicine September 12-14, 2016 Berlin, Germany

Reprogramming of cardiomyocytes require severe interference with normal signaling and cellular homeostasis. In contrast with molecular vectors and scientifically highly disputable stimulus triggered acquired pluripotency (STAP), use mechanical stress for induction which seems to induce regeneration by reiterating embryonic developmental pathways. Here, we show that epigenetic signaling via hemodynamic mechanotransduction on human venous vascular cells in cardiomyopathy hearts induces pluripotency marker Klf4, but not NANOG. Pressure controlled intermittent coronary sinus occlusion (PICSO) temporarily increases shear stress during backflow in cardiac microcirculation and via mechanical stretch of elevated pressures on vascular cells including pericytes create a pleiotropic signaling known as canonical pathway during morphogenesis of theheart. This intervention was applied in patients with end stage cardiomyopathy for 20 minutes. Sera of coronary sinus blood samples were co-cultured with human cardiomyocytes explanted from a patient with end stage cardiomyopathy during heart transplantation. Klf4 expression was measured as pluripotency marker. Sera of treated patients were able to significantly upregulate Klf4 in cultured cardiomyocytes as compared to those taken before treatment and in untreated controls. In porcine myocardial specimen subjected to acute ischemia with and without PICSO also a significant increase of Ki67 and a reduction of p53 were observed. This indicates that direct mechanotransduction as well as the release of soluble factors act in accordance in the recovery of failing hearts mimicking similar pathways known during the development of the heart. We conclude that the STAP concept might have been abolished too early and that a clinically feasible transcoronary sinus intervention may inducea paradigm change in regeneration therapy.

Denis Barritault graduated in Physics, completed his PhD in biochemistry in Paris University. Post-doctoral in molecular immunology at Pasteur Institute and NYU as NIH Fogarty Fellow he joined INSERM unit in Paris as developmental biologist. He made the first description and patents of FGF extracted from retina in 1979 and 82 as skin and cornea healing agent, became full professor at Paris-Est University in 1985, founded and directed a CNRS Laboratory on cell and tissue regeneration until 2003. He is now President of OTR3, Emeritus professor, honorary director CRRET CNRS unit and author in over 200 publications and 30 patents.

Extra Cellular Matrix (ECM) microenvironment regulates locally our continuous ability to replace dead cells by new cells. This central law of all living is known as tissue homeostasis. Heparan sulfates (HS) are key elements of the ECM scaffold that store, protect and position the various Cell Communication Peptides (CCP) in the cellular microenvironment. HS play a pivotal role in the regulation of the bioavailability of CCP, cell proliferation, migration and differentiation required for tissue regeneration. Tissue injury will lead to destruction of cells and surrounding ECM. CCP released by inflammatory and circulating cells can then promote tissue repair, but with a loss of tissue quality, leaving scars or fibrosis. We have engineered biodegradable nano-polysaccharide mimicking HS, named RGTA for ReGeneraTing Agent. Introduced at the site of injury,RGTA will bind to the matrix proteins of the damaged ECM, and to the CCP produced by healthy neighboring cells, thereby restoring the ECM microenvironment and conditions for tissue homeostasis. This matrix therapy approach has considerably improved the quality of healing in various animal models with reduction or absence of fibrosis resulting in a real regeneration process. The RGTA technology has been validated in clinics and over hundred thousand of patients treated both for corneal and skin ulcers with no adverse effect. Adapted RGTA are in development for more tissue injuries extending RGTA as a new therapeutic class in the field of regenerative medicine exploiting our natural potential without need for exogenous cells. RGTA can combine with cell therapy by constructing a niche to favor homing. The future of regenerative medicine lays in a proper adjustment of the microenvironment to optimize cell colonization, expansion, replacement and recovery of their functions.

Bertha Chen has completed her Bachelor of Science degree in Chemical Engineering from the University of California, Berkeley and Doctorate of Medicine from Stanford University School of Medicine. She is a Professor of Ob/Gyn and Urology (by courtesy) at Stanford University School of Medicine and Co-Chief of the Division of Urogynecology and Pelvic Reconstructive Surgery. Her research focus is in stem cell pluripotency, mesenchymal differentiation and stem cell based therapy for urinary incontinence. She has published more than 55 papers in reputed journals.

Stem cell research and regenerative medicine are integral to the field of Obstetrics and Gynecology. With the explosion of technologies directed at treatments for infertility, there is a critical need to understand properties of pluripotency and how it relates to embryo development. Evidence of cancer stem cells will drive new discoveries in the treatment of gynecologic malignancies such as ovarian and endometrial cancers. Notably, there is great interest in regeneration of aged or damaged tissues specific to the female anatomy and lower urinary tract via stem cell based technologies. In humans, damaged tissues are generally replaced by continuous recruitment and differentiation from stem cells in the body. However, the body’s ability for regeneration is reduced with aging. Examples of conditions in need of regenerative therapies are urinary and fecal incontinence resulting from sphincter deficiency and pelvic organ prolapse. These conditions are prevalent in older women and greatly affect quality of life and represent colossal health costs. Current approaches for tissue regeneration include transplantation of adult mesenchymal cells or their derivatives and implantation of engineered scaffolds seeded with these cells. Induced pluripotent stem cells are a promising source of autologous cells. Because of their property of self-renewal, large amounts of cells can be produced for transplantation. Furthermore, their pluripotent state allows for derivation of multiple cell types thus facilitating implementation in a stepwise fashion from simple cell injections to more elaborate matrices with multiple cell types that have potential for full regeneration. Here, we discuss stem cell based approaches for tissue regeneration in obstetrics and gynecology.

Cartilage is a tissue with a huge complexity, which is present in the human body in three types: Hyaline cartilage, fibrocartilage and elastic cartilage. Apart from some resemblances, these types are quite different and play unlike roles for human functionality. For instance, the hyaline cartilage, also known as articular cartilage, has a major role in providing joints with a surface that combines low friction with high lubrication. On the other hand, fibro-cartilage (e.g. in the temporomandibular joint disc) spreads the intra-articular load, stabilizes the joints during translation and decreases the wear of the articular surface. Even though, getting a deeper knowledge on cartilage characterization and understanding, bridging the gap between anatomy and physiology, may lead the way for better implants aiming cartilage repair and regeneration. This is of even more interest as cartilage is an avascular tissue of the human body, hence with an extremely low capability for tissue regeneration. However, this ground-breaking issue can only be successful achieved with the establishment of multidisciplinary research teams. Thus, several processes have been tested to assemble tailored and optimized constructs that could endorse cartilage repair and regeneration. These processes advantages, drawbacks, results and capabilities will be presented and discussed.