Human Liver Cells Expressing Albumin and Mesenchymal Characteristics Give Rise to Insulin-Producing Cells

Abstract

Activation of the pancreatic lineage in the liver has been suggested as a potential autologous cell replacement therapy for diabetic patients. Transcription factors-induced liver-to-pancreas reprogramming has been demonstrated in numerous species both in vivo and in vitro. However, human-derived liver cells capable of acquiring the alternate pancreatic repertoire have never been characterized. It is yet unknown whether hepatic-like stem cells or rather adult liver cells give rise to insulin-producing cells. Using an in vitro experimental system, we demonstrate that proliferating adherent human liver cells acquire mesenchymal-like characteristics and a considerable level of cellular plasticity. However, using a lineage-tracing approach, we demonstrate that insulin-producing cells are primarily generated in cells enriched for adult hepatic markers that coexpress both albumin and mesenchymal markers. Taken together, our data suggest that adult human hepatic tissue retains a substantial level of developmental plasticity, which could be exploited in regenerative medicine approaches.

The Wnt/β‐catenin pathway determines the predisposition and efficiency of liver‐to‐pancreas reprogramming

“…Rather, these cells originated from differentiated adult cells with distinct metabolic function that possess developmental plasticity. However, due to the mesenchymal nature of human liver cells that have undergone EMT in vitro , and the technical challenge to trace human‐derived cells, we cannot unequivocally suggest that the human liver cells, which are predisposed to TD, indeed originate from adult human pericentral liver cells.…”

“…In in vitro culture, proliferating human liver cells undergo dedifferentiation and epithelial‐to‐mesenchymal transition . However, our data suggest that these primary cultures of proliferating human liver cells retain, at least partially, the heterogeneity in Wnt signaling, which is in vivo related to the liver zonation.…”

“…In vitro lineage tracing was performed by a modified dual lentivirus system as described previously . Cells derived from >15 different donors (age range, 3‐60 years) were treated by both lentiviruses.…”

Restoring insulin production for type 1 diabetes

“…Transplantation of the Pdx1 ‐treated liver cells under the kidney capsule of immunocompromised mice ameliorated hyperglycemia throughout the 2‐month study. Subsequently, the same group demonstrated, with lineage tracing, that the liver‐derived insulin‐secreting cells originated mainly from albumin‐positive cells 89 . In parallel, the ectopic expression of Nkx6.1 in human liver cells by in vitro adenoviral infection resulted in the activation of several pancreatic transcription factors and a modest increase in insulin expression 90 .…”

Insulin Promotes Glucose Consumption via Regulation of miR-99a/mTOR/PKM2 Pathway

“…It has been demonstrated that insulin can regulate glucose metabolism by activating mTOR pathway [19], [20]. The liver is known to be important in regulating glucose metabolism in response to growth factors and insulin treatment [21], [22]. With the co-treatment of saffron and insulin, mTOR pathway improves the insulin sensitivity [23].…”