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Home All Updates (139) Stem cell Portal Ma
Stem cell Portal March 21, 2018 Mending broken hearts with cardiomyocyte molds Whether caused by an undetected birth defect or by a heart attack (myocardial infarction), when a heart sustains damage it can be difficult to repair. If heart muscle cells — cardiomyocytes — could be repaired by cells taken from one’s own body, the patient's recovery improves. But manufacturing heart cells requires an exacting process tailored specifically to an individual. In a study published recently in Advanced Functional Materials, a team of researchers at Michigan Technological University in collaboration with Harvard Medical School shows how cardiomyocytes grown in a heart-like environment mature more quickly, have improved functionality and are less likely to be rejected by patients’ bodies. Many people with heart injuries from heart attacks or birth defects could benefit from the “self-therapeutic” process of injecting healthy cells into the damaged heart muscle. Labs use induced pluripotent stem cells (iPSCs), which using biochemical cues can be “programmed” to become any type of cell, whether for the heart muscle or otherwise. Yet current processes result in underdeveloped cells. To date, manufacturing cardiomyocytes has occurred in two-dimensional settings (essentially, petri dishes). But the growth environment plays a large role in the ways the cells develop. Thus, simulating the actual heart environment — with lots of pressure and specific forces acting on the growing cells — could lead to more robust cardiomyocytes. “Unfortunately stem cell therapeutics don’t have high success rates, partly because the cells are not mature and fully functional. The maturation and functionality are essential, ” said Parisa Pour Shahid Saeed Abadi, Ph.D., assistant professor of mechanical engineering, whose work in creating heart cell growth environments is detailed in the study. Mimicking the natural heart environment Dr. Abadi and her co-authors have created three-dimensional substrates — essentially, molds — that recreate the environment in which heart cells grow inside the human body. Biomechanical properties the substrates induce include pressure and stiffness. “The mechanical properties of substrates play an important role in the cell behavior because the mechanical cues that cells sense in the actual (heart) environment is unique, ” Dr. Abadi said. “We are using biochemical and biomechanical cues to enhance the differentiation and maturation. If we don’t take advantage of the physical cues and only rely on chemical cues, the process suffers from low efficiency and batch-to-batch inconsistency.” Using photolithography and reflow processing, Dr. Abadi’s substrates are patterned at the micron and submicron levels, approximating the natural physical forces cells experience. Photolithography uses ultraviolet light to remove portions of polydimethylsiloxane (PDMS) substrate to mold it into cylindrical shapes. Additional micro-patterning of the substrate changes the cytoskeleton in the cell and the shape of the nucleus, which cause the genes in the cell to change. As the cardiomyocytes mature, they beat stronger and resemble the cells found in natural, mature heart muscle. “On day one we start seeing the effect of the substrate on the morphology of the cells, ” Dr. Abadi said. Abadi’s lab continues to improve the substrate preparation methods. As cardiomyocytes need to communicate with each other during their growth, Dr. Abadi also plans to stimulate electrical conductivity between cells. Translational studies in animals are the next step for the research. These lab-fabricated, fluorescently stained cardiomyocytes — heart muscle cells — exhibit the maturation and functionality of heart cells grown within a heart. Induced pluripotent stem cell-derived cardiomyocytes beating in substrate.
  • 2018-04-02T15:04:14

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Gene editing can help treat congenital disease before birth Updated Oct 09, 2018 | 20:02 IST | IANSPrenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders. Representational image Photo Credit: ThinkstockRepresentational Image New York: In a first, a team of scientists have performed prenatal gene editing to prevent a lethal metabolic disorder in laboratory mice, offering the potential to treat human congenital diseases before birth. The study led by research from Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania used both CRISPR-Cas9 and base editor 3 (BE3) gene-editing tools and reduced cholesterol levels in healthy mice treated in utero by targeting a gene that regulates those levels. They also used prenatal gene editing to improve liver function and prevent neonatal death in a subgroup of mice that had been engineered with a mutation causing the lethal liver disease hereditary tyrosinemia type 1 (HT1). Advertising Advertising HT1 in humans usually appears during infancy, and it is often treatable with a medicine called nitisinone and a strict diet. However, when treatments fail, patients are at risk of liver failure or liver cancer. Prenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders. "Our ultimate goal is to translate the approach used in these proof-of-concept studies to treat severe diseases diagnosed early in pregnancy, " said William H. Peranteau, a paediatric and foetal surgeon at CHOP. "We hope to broaden this strategy to intervene prenatally in congenital diseases that currently have no effective treatment for most patients, and result in death or severe complications in infants, " he added. In the study, published in the journal Nature Medicine, the team used BE3, joined it with a modified CRISPR-associated protein 9. After birth, the mice carried stable amounts of edited liver cells for up to three months after the prenatal treatment, with no evidence of unwanted, off-target editing at other DNA sites. In the subgroup of the mice bio-engineered to model HT1, BE3 improved liver function and preserved survival. However, "a significant amount of work needs to be done before prenatal gene editing can be translated to the clinic, including investigations into more clinically relevant delivery mechanisms and ensuring the safety of this approach", said Peranteau. He added: "Nonetheless, we are excited about the potential of this approach to treat genetic diseases of the liver and other organs for which few therapeutic options exist."
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