A macromolecule that prevents the shortening of telomeres — the protective caps connected the ends of chromosomes — helps bosom musculus cells derived from patients with Duchenne muscular dystrophy unrecorded longer and look healthier successful a laboratory dish, according to a survey by researchers astatine Stanford Medicine.
The uncovering is notable arsenic bosom nonaccomplishment caused by nonaccomplishment of these cells, called cardiomyocytes, is the starring origin of decease for radical with the disease.
“One of the astir unexpected findings successful our erstwhile probe is that telomeres shorten implicit clip successful cardiomyocytes successful the hearts of radical with Duchenne muscular dystrophy,” said Helen Blau, PhD, prof of microbiology and immunology. “Now we amusement that we tin forestall that shortening successful a laboratory dish, and erstwhile we bash so, the diseased cardiomyocytes statesman to lucifer those from steadfast people. They besides unrecorded longer.”
The cells’ melodramatic turnaround was not anticipated.
“We had hoped to spot an summation successful cardiomyocyte longevity, based connected our erstwhile research,” said Asuka Eguchi, PhD, an teacher successful the Stanford Cardiovascular Institute and a subordinate of Blau’s lab. “But we were rather amazed to besides spot specified an betterment successful the quality of the cells, some successful their size and successful the prevalence of the proteins that let musculus cells to contract. Premature nonaccomplishment of cardiomyocytes leads to scarring and stiffening of the bosom insubstantial and importantly impairs its function. Now we’re homing successful connected a strategy to combat this damage.”
Blau, who is besides the Donald E. and Delia B. Baxter Foundation Professor and manager of the Baxter Foundation Laboratory for Stem Cell Biology, is the elder writer of the research, which was published online Jan. 31 successful the Proceedings of the National Academy of Sciences. Eguchi is the pb writer of the study.
A shortened life
About 1 successful 5,000 boys are calved with Duchenne muscular dystrophy, which is caused by a mutation successful a cistron for a macromolecule called dystrophin. Dystrophin connects the wrong of musculus cells to proteins and different molecules connected structures extracurricular the cell, enabling muscles to declaration properly. Without dystrophin, the muscles progressively weaken, and patients usually dice successful young adulthood owed to bosom and breathing difficulties.
Telomeres are often thought of arsenic the body’s molecular timepiece due to the fact that they shorten somewhat each clip a compartment divides. When they get excessively short, the compartment stops dividing and dies. Until recently, however, they’ve been thought to beryllium mostly unchangeable successful cells similar cardiomyocytes, which disagreement infrequently. But probe from Blau’s laboratory successful 2016 and 2018 recovered that radical with Duchenne muscular dystrophy, arsenic good arsenic those with a benignant of bosom nonaccomplishment called cardiomyopathy, person telomeres that are betwixt 25% and 40% shorter than those successful steadfast people.
The abnormally shortened telomeres activate a harm effect that interferes with the cells’ vigor centers and hampers the heart’s quality to pump humor passim the body, the researchers found. In this study, they sought ways to combat that.
“We wanted to spot if we could re-create this telomere shortening successful a laboratory crockery and whether we mightiness beryllium capable to forestall it,” Eguchi said.
The researchers utilized induced pluripotent stem cells generated from 2 radical with Duchenne muscular dystrophy to marque cardiomyocytes with mutations successful the dystrophin gene. (Induced pluripotent stem cells tin beryllium made from tegument oregon different cells collected painlessly from radical and tin beryllium coaxed successful a laboratory crockery to go astir immoderate benignant of compartment successful the body.) They grew the cardiomyocytes successful a laboratory crockery and observed however they looked and functioned compared with steadfast cells successful which the dystrophin mutation had been genetically corrected successful the laboratory. The cells were different genetically identical.
They saw that the diseased cardiomyocytes were astir 40% smaller than the cells successful which the dystrophin mutation had been corrected. The patterns of troponin — a calcium-binding macromolecule connected the filaments that nutrient musculus contraction — were besides little dense than those seen successful steadfast cells.
Chromosome guards
Telomeres are made up of the aforesaid gathering blocks, called nucleotides, of the genes they protect. But alternatively than coding for proteins, they incorporate a circumstantial series of six nucleotides repeated hundreds oregon thousands of times connected the ends of chromosomes. These repeats service arsenic a carnal buffer, protecting the ends of the chromosomes from the shortening that people occurs during the DNA replication that precedes compartment division. After a finite fig of compartment divisions, the shrinking telomeres trigger a authorities of cellular hibernation and eventual decease — efficaciously limiting the lifespan of astir quality cells.
Telomeres, successful turn, are protected by a radical of respective proteins that signifier a operation called shelterin, which guards against harm and regulates the enactment of a telomere-lengthening protein, telomerase, that is progressive successful stem cells and successful immoderate crab cells.
The researchers recovered that exposing the diseased cardiomyocytes to TRF2, a shelterin protein, prevented the telomeres from shortening. It besides accrued the fig of cells that survived much than 30 days.
“We saw these beauteous morphological changes,” Eguchi said, “as good arsenic an summation successful the density of troponin, a macromolecule that is simply a cardinal constituent of the filaments that marque up the contractile apparatus. We are excited astir the anticipation of 1 time utilizing a akin attack to support telomeres successful patients with Duchenne muscular dystrophy oregon possibly adjacent different types of cardiomyopathy.”
The researchers caution, however, that overmuch much probe needs to beryllium conducted to larn whether overexpression of TRF2 would beryllium harmless and effectual successful radical with these conditions. “This would person to beryllium a cautiously targeted cistron therapy,” Eguchi said, “because determination is grounds that exposing dividing cells to TRF2 tin origin a batch of havoc successful the body.”
A TRF2-based cistron therapy besides would not code the origin of Duchenne muscular dystrophy, which is the deficiency of the dystrophin macromolecule passim the body.
“This unsocial could not cure the disease,” Blau said. “But it could possibly ameliorate the bosom nonaccomplishment experienced by these patients. Ideally, we would 1 time beryllium capable to springiness a operation therapy that some restores the quality to nutrient dystrophin and helps support the viability of the cardiomyocytes.”
The survey was funded by the National Institutes of Health (grants R01 HL126527, R01 HL130020, R01 HL123968, R01 HL146690 and R01 HL159340), the American Heart Organization, the Muscular Dystrophy Association, the California Institute for Regenerative Medicine, the Keck Foundation, the Baxter Foundation, the Li Ka Shing Foundation, the Tobacco-Related Disease Research Foundation, a Stanford School of Medicine dean’s postdoctoral fellowship, a Stanford Translational Research and Applied Medicine aviator grant, and the Stanford Bio-X Summer Undergraduate Research Program.
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