Stem Cell Differentiation Triggers Could Aid Development of Regenerative Muscle Therapy

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A study led by researchers at the University of California (UC) San Diego Jacobs School of Engineering has offered up new insights into the mechanisms of stem cell differentiation that could one day help scientists develop regenerative therapies for muscle disease, injury and atrophy. By studying how easily different pluripotent stem cell lines differentiated into muscle cells, and comparing time-dependent changes in the cells’ transcriptomic profiles, the researchers discovered epigenetic mechanisms that can be triggered to accelerate muscle cell growth at different stages of stem cell differentiation.

“Stem cell-based approaches that have the potential to aid muscle regeneration and growth would improve the quality of life for many people, from children who are born with congenital muscle disease to people who are losing muscle mass and strength due to aging,” said Shankar Subramaniam, PhD, distinguished professor of bioengineering, computer science and engineering, and cellular and molecular medicine at UC San Diego and lead corresponding author of the team’s study, which is published in Science Advances. “Here, we have discovered that specific factors and mechanisms can be triggered by external means to favor rapid growth.” Subramaniam and colleagues report their findings in a paper titled, “Temporal mechanisms of myogenic specification in human induced pluripotent stem cells.”

Human induced pluripotent stem cells (hIPSCs) could feasibly be used to create new muscle tissue, and generate or repair skeletal muscle for patients with skeletal muscle diseases. However, different hIPSC cell lines show different levels of ability to differentiate into myocytes, and so scientists need to better understand the mechanisms of myogenesis in hIPSCs. “hiPSCs of different origin show distinctive kinetics and ability to differentiate into myocytes,” the authors noted. “Understanding the mechanisms of myogenesis in human induced pluripotent stem cells (hiPSCs) is a prerequisite to achieving patient-specific therapy for diseases of skeletal muscle.”

To try and identify mechanisms that prompt fast, robust differentiation of hIPSCs into muscle cells, the UCSD researchers studied how time-related changes in the transcriptome profiles of three different hIPSC cell lines that can differentiate into myocytes. One of the cell lines grew into muscle much faster than the other two, so the researchers looked at what factors made this line different from the rest, and then induced these factors in the other lines to see if they could accelerate muscle growth.

They found that triggering several epigenetic mechanisms at different time points sped up muscle growth in the slower of the pluripotent stem cell lines. More specifically, muscle growth in these cell lines was increased by inhibiting a gene called ZIC3 at the outset of differentiation—“… we show that targeted knockdown of ZIC3 at the outset of differentiation leads to improved myogenic specification in blunted hiPSC lines”— followed by then adding beta-catenin transcriptional cofactors later on in the growth process. “… our analyses and perturbation experiment suggest the key role played by the beta-catenin cofactors at the outset of differentiation and on downstream targets for myogenic differentiation,” they noted.

The team says the results of their study to compare the multiple hiPSC lines offers up a unique transcriptomic dataset. “We detailed gene expression patterns related to transcriptional, signaling pathway, and epigenetic regulation that lead to robust myogenic specification,” they added. “Together, our study is a framework to better understand and potentially improve myogenic specification of hiPSCs.”

“A key takeaway here is that all pluripotent stem cells do not have the same capacity to regenerate,” Subramaniam said. “Identifying factors that will prime these cells for specific regeneration will go a long way in regenerative medicine.”

The team plans to explore therapeutic intervention, such as drugs, that can stimulate and accelerate muscle growth at different stages of differentiation in hIPSC. They will also see whether implanting specific pluripotent stem cells in dystrophic muscle can stimulate new muscle growth in animals. Ultimately, the goal is to investigate if such a stem cell-based approach could regenerate muscle in aging humans.

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