Hepatocyte A1ATD

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DefiniGEN provide disease modelled alpha-1 antitrypsin deficiency hepatocytes which are highly functional patient-derived human hepatocytes. The cells are generated using the dermal fibroblasts from an alpha-1 antitrypsin (A1AT) disorder patient carrying the ‘Z’ (E342K) point mutation in the A1AT gene SERPINA1. This mutation leads to the formation of mutant A1AT polymers that ultimately cause liver and lung damage. DefiniGEN’s A1AT patient derived hepatocytes represent an optimized disease model for drug discovery applications and are an effective tool for elucidating the underlying mechanisms of the disease.


Reprogramming of patient derived A1ATD fibroblasts into iPSCs and differentiation of iPSCs into A1ATD hepatocytes


Figure 1. For production of DefiniGEN’s A1ATD cells, A1AT patient fibroblasts are first reprogrammed into iPSC using Nobel prize winning technology developed by Yamanaka and colleagues. These iPSC are then differentiated into liver hepatocytes using the OptiDIFF protocol developed at the University of Cambridge-Laboratory for Regenerative Medicine.

  • Highly standardized cell product containing >98% human hepatocyte cells with consistent performance and biologically relevant data
  • Disease circuit verified ZZ E342K mutation in the SERPINA1 gene

Def-HEP A1ATD cell morphology

The Def-HEP A1ATD cells are highly functional human hepatocytes. When thawed and plated as a monolayer Def-HEP A1ATD cells form with typical hepatocyte cobblestone morphology.

Clear cobblestone morphology of A1AT disease modelled hepatocytes

Figure 2. Clear cobblestone morphology of Cryo-Def HEP (A1AT) post thaw and recovery. Cell seeding density: 1×106 cells/mL in collagen type 1 coated 24 well plate. Confluent monolayer. Magnification level: x10.

Hepatocyte maturation markers

Def-HEP A1ATD cells display the functional characteristics of primary human hepatocytes (PHH) including albumin and A1AT production (Figure 2). Accordingly, they should be handled in a similar fashion to primary human hepatocytes.

Immunostaining for expression of A1AT polymers and total A1AT in A1ATD hepatocytes and control PHH.


Figure 3. Immunostaining for expression of A1AT polymers (2c1mAb) and total A1AT in Def-HEP A1ATD and PHH.

Detection of disease markers via ELISA

ELISA for polymer and secreted A1AT using antibodies specific for A1AT polymers (2C1mAb, top) or all conformers of A1AT (bottom).

ELISA quantificaiton of intracellular A1AT polymers in A1ATD hepatocytes, Primary human hepatocytes (PHH) and hepatocellular liver carcinoma cells (HepG2).

Percent secretion of total A1AT by A1ATD hepatocytes and primary human hepatocytes

Figure 4. Def-HEP A1ATD represents the cryopreservation sample. Primary human hepatocytes (PHH) and hepatocellular liver carcinoma cells (HepG2) are used as internal controls. PHH and HepG2 show A1AT polymer levels below the limit of quantification.

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