title: Elevated hepatocyte-specific functions in fetal rat hepatocytes co-cultured with adult rat hepatocytes.
abstract: Fetal hepatocytes (FHEPs) are a potential source of highly proliferative transplantable cells but express low levels of liver-specific functions. We hypothesized that the microenvironment of adult hepatocytes (AHEPs) may upregulate these functions. Primary FHEPs were seeded on top of collagen-sandwiched AHEPs directly or separated by a porous transwell membrane insert. In direct co-cultures, albumin (ALB) secretion, urea synthesis, and cytochrome P450 (CytP450) activity were all approximately 2 times as high as the sum of the corresponding monocultures. Using a transwell porous insert led to similar results, suggesting a major role for soluble factors. When AHEPs and FHEPs were separated after co-culture, they both initially showed significantly higher ALB secretion than control monocultures, whereas urea synthesis was significantly lower for the FHEPs only. Functions of previously co-cultured FHEPs normalized over the course of a week, but AHEP function remained high even after separation. In conclusion, co-culturing AHEPs with FHEPs increases expression of liver-specific functions in both cell types. The effect on FHEPs, but not AHEPs, was reversible. Unraveling the underlying mechanisms and optimizing this phenomenon will be useful in making fetal liver cells a potential cell source for hepatic tissue-engineering applications.
authors.affiliation: Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Burns Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Daan
authors.initials: D
authors.lastname: van Poll
authors.forename: Cenk
authors.initials: C
authors.lastname: Sokmensuer
authors.forename: Noor
authors.initials: N
authors.lastname: Ahmad
authors.forename: Arno W
authors.initials: AW
authors.lastname: Tilles
authors.forename: François
authors.initials: F
authors.lastname: Berthiaume
authors.forename: Mehmet
authors.initials: M
authors.lastname: Toner
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
mesh_terms: D000375:Aging / Q000473:pathology* / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods*; D005260:Female; D022781:Hepatocytes / Q000166:cytology* / Q000502:physiology*; D008111:Liver Function Tests; D051381:Rats; D011917:Rats, Inbred Lew; D023822:Tissue Engineering / Q000379:methods*