A collaborative group of scientists from the Center for Regenerative Medicine (CReM) at Boston University (BU), Boston Medical Center (BMC), and Children’s Hospital of Philadelphia (CHOP) have generated a new stem cell line that recapitulates a disease signature that may help explain how an abnormal protein leads to liver disease. The researchers developed the induced pluripotent stem cell (iPSC) model while studying the genetic lung/liver disease called alpha-1 antitrypsin (AAT) deficiency— a common genetic cause of both liver and lung disease affecting an estimated 3.4 million people worldwide. 

The investigators found that liver cells derived from AAT-deficient iPSCs were more sensitive to drugs that cause liver toxicity than liver cells derived from normal iPSCs. The researchers are optimistic that this discovery will lead to new therapeutic interventions for this condition.

IPSCs are derived from the donated skin or blood cells of adults and can be reprogrammed back to an embryonic stem cell-like state—allowing for the differentiation toward any cell type in the body. The researchers created iPSCs with AAT deficiency and forced them to differentiate into liver-like cells. The scientists studied the induced hepatic cells and found they secreted AAT protein much more slowly than normal cells or iPSCs without the AAT deficiency that were induced into hepatic cells—demonstrating that the iPSC model recapitulates a critical aspect of the disease as it occurs in patients. Moreover, the AAT deficiency is caused by a mutation in a single DNA base and upon correcting this single base back to the normal sequence, the investigators found that the abnormal secretion was rectified.

“We found that these corrected cells had a normal secretion kinetic when compared with their diseased, parental cells that are otherwise genetically identical except for this single DNA base,” explained lead author Andrew Wilson, M.D., assistant professor of medicine at Boston University School of Medicine and Director of the Alpha-1 Center at BU and BMC.

The findings from this study were published in April in Stem Cell Reports through an article entitled “Emergence of a Stage-Dependent Human Liver Disease Signature with Directed Differentiation of Alpha-1 Antitrypsin-Deficient iPS Cells.”

Interestingly the scientists found that AAT-deficient iPSC-liver cells were more sensitive to certain drugs than those derived from normal cells.“This is important because it suggests that the livers of actual patients with this disease might be more sensitive in the same way,” noted Dr. Wilson.

“The disease-specific cells display intracellular accumulation of mutant AAT protein, resulting in increased autophagic flux,” the authors explained. “Furthermore, we detect beneficial responses to the drug carbamazepine, which further augments autophagic flux, but adverse responses to known hepatotoxic drugs. Our findings support the utility of iPSCs as tools for drug development or prediction of toxicity.”

The researchers were excited by their findings and believe that studies using patient-derived stem cells will allow them to uncover how patients with AAT deficiency develop liver disease.

“We hope that the insights we gain from these studies will result in the discovery of new potential treatments for affected patients in the near future,” concluded Dr. Wilson.

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