title: Human placenta hydrogel reduces scarring in a rat model of cardiac ischemia and enhances cardiomyocyte and stem cell cultures.
abstract: Xenogeneic extracellular matrix (ECM) hydrogels have shown promise in remediating cardiac ischemia damage in animal models, yet analogous human ECM hydrogels have not been well development. An original human placenta-derived hydrogel (hpECM) preparation was thus generated for assessment in cardiomyocyte cell culture and therapeutic cardiac injection applications.
  
  
  
  Hybrid orbitrap-quadrupole mass spectrometry and ELISAs showed hpECM to be rich in collagens, basement membrane proteins, and regenerative growth factors (e.g. VEGF-B, HGF). Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes synchronized and electrically coupled on hpECM faster than on conventional cell culture environments, as validated by intracellular calcium measurements. In vivo, injections using biotin-labeled hpECM confirmed its spatially discrete localization to the myocardium proximal to the injection site. hpECM was injected into rat myocardium following an acute myocardium infarction induced by left anterior descending artery ligation. Compared to sham treated animals, which exhibited aberrant electrical activity and larger myocardial scars, hpECM injected rat hearts showed a significant reduction in scar volume along with normal electrical activity of the surviving tissue, as determined by optical mapping.
  
  
  
  Placental matrix and growth factors can be extracted as a hydrogel that effectively supports cardiomyocytes in vitro, and in vivo reduces scar formation while maintaining electrophysiological activity when injected into ischemic myocardium.
  
  
  
  This is the first report of an original extracellular matrix hydrogel preparation isolated from human placentas (hpECM). hpECM is rich in collagens, laminin, fibronectin, glycoproteins, and growth factors, including known pro-regenerative, pro-angiogenic, anti-scarring, anti-inflammatory, and stem cell-recruiting factors. hpECM supports the culture of cardiomyocytes, stem cells and blood vessels assembly from endothelial cells. In a rat model of myocardial infarction, hpECM injections were safely deliverable to the ischemic myocardium. hpECM injections repaired the myocardium, resulting in a significant reduction in infarct size, more viable myocardium, and a normal electrophysiological contraction profile. hpECM thus has potential in therapeutic cardiovascular applications, in cellular therapies (as a delivery vehicle), and is a promising biomaterial for advancing basic cell-based research and regenerative medicine applications.
authors.affiliation: LifeNet Health Institute of Regenerative Medicine, Virginia Beach, VA, United States; Eastern Virginia Medical School, Norfolk, VA, United States. Electronic address: mpf3b@virginia.edu.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Francis
authors.affiliation: LifeNet Health Institute of Regenerative Medicine, Virginia Beach, VA, United States. Electronic address: erick_breathwaite@lifenethealth.org.
authors.forename: Erick
authors.initials: E
authors.lastname: Breathwaite
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United States. Electronic address: abulyshe@odu.edu.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Bulysheva
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United States; Department of Electrical and Computer Engineering, Old Dominion University, Norfolk, VA, United States. Electronic address: fvarg001@odu.edu.
authors.forename: Frency
authors.initials: F
authors.lastname: Varghese
authors.affiliation: LifeNet Health Institute of Regenerative Medicine, Virginia Beach, VA, United States. Electronic address: rudy_rodriguez@lifenethealth.org.
authors.forename: Rudy U
authors.initials: RU
authors.lastname: Rodriguez
authors.affiliation: Eastern Virginia Medical School, Norfolk, VA, United States. Electronic address: duttasm@evms.edu.
authors.forename: Sucharita
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United States.
authors.forename: Iurii
authors.initials: I
authors.lastname: Semenov
authors.affiliation: LifeNet Health Institute of Regenerative Medicine, Virginia Beach, VA, United States. Electronic address: Rebecca_ogle@lifenethealth.org.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ogle
authors.affiliation: LifeNet Health Institute of Regenerative Medicine, Virginia Beach, VA, United States. Electronic address: alexander_huber@lifenethealth.org.
authors.forename: Alexander
authors.initials: A
authors.lastname: Huber
authors.affiliation: FH Campus Wien, Applied Life Sciences, Wien, Austria.
authors.forename: Alexandra-Madelaine
authors.initials: AM
authors.lastname: Tichy
authors.affiliation: LifeNet Health Institute of Regenerative Medicine, Virginia Beach, VA, United States.
authors.forename: Silvia
authors.initials: S
authors.lastname: Chen
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United States; Department of Electrical and Computer Engineering, Old Dominion University, Norfolk, VA, United States. Electronic address: czemlin@odu.edu.
authors.forename: Christian
authors.initials: C
authors.lastname: Zemlin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000737:chemistry*; D005260:Female; D048091:Guided Tissue Regeneration / Q000379:methods*; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D008297:Male; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D010920:Placenta / Q000737:chemistry*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
chemical_list: D020100:Hydrogels
keywords: Cardiomyocyte culture; Decellularized; Extracellular matrix; Hydrogel; Ischemia; Placenta