Dedifferentiation of human hepatocytes by extracellular matrix proteins in vitro: quantitative and qualitative investigation of cytokeratin 7, 8, 18, 19 and vimentin filaments

Blaheta, Roman A.; Kronenberger, Bernd; Woitaschek, Dirk; Auth, Marcus; Scholz, Martin; Weber, Stephan; Schuldes, H.; Encke, A.; Markus, B. H.

doi:10.1016/s0168-8278(98)80293-6

Cited by 46 publications

(38 citation statements)

References 43 publications

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“…The expression of K19 and ␤1 integrin and p63 are inducible under cell culture conditions and are associated with expanded proliferative capacity (Pellegrini et al, 2001;Risse Marsh et al, 2002;Harkin et al, 2004;Joseph et al, 2004;Kim et al, 2004). In other systems, the generation of ␤1 integrin and K19 cell islands in the spinous and granular layers of the human epidermis is believed to be the product of dedifferentiation, as is K19 expression within human mammary ductal cells and hepatocytes (Blaheta et al, 1998;Fu et al, 2001;Helczynska et al, 2003). Similarly, adult rabbit corneal epithelial cells can be reprogrammed to generate fully differentiated epidermis, hair follicles, and sweat glands (Ferraris et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Localization of candidate stem and progenitor cell markers within the human cornea, limbus, and bulbar conjunctiva in vivo and in cell culture

Vascotto

Griffith

2006

Anat. Rec.

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Corneal diseases are some of the most prevalent causes of blindness worldwide. While the most common treatment for corneal blindness is the transplantation of cadaver corneas, expanded limbal stem cells are finding recent application. Unknown, however, is the identity of the actual repopulating stem cell fraction utilized in both treatments and the critical factors governing successful engraftment and repopulation. In order to localize potential stem cell populations in vivo, we have immunohistochemically mapped a battery of candidate stem and progenitor cell markers including c-Kit and other growth factor receptors, nuclear markers including ⌬Np63, as well as adhesion factors across the cornea and distal sclera. Cell populations that differentially and specifically stained for some of these markers include the basal and superficial limbal/conjunctival epithelium and scattered cells within the substantia propria of the bulbar conjunctiva. We have also determined that the culture of differentiated cornea epithelial cells as dissociated and explant cultures induces the expression of several markers previously characterized as candidate limbal stem cell markers. This study provides a foundation to explore candidate corneal stem cell populations. As well, we show that expression of traditional stem cell markers may not be reliable indicator of stem cell content during limbal stem cell expansion in vitro and could contribute to the variable success rates of corneal stem cell transplantation. Anat Rec Part A, 288A: 921-931, 2006.

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Section: Discussionmentioning

confidence: 99%

Localization of candidate stem and progenitor cell markers within the human cornea, limbus, and bulbar conjunctiva in vivo and in cell culture

Vascotto

Griffith

2006

Anat. Rec.

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Section: Discussionmentioning

confidence: 99%

“…This is of particular importance, as healthy, physiologically intact hepatocytes are characterized by stable CK18 expression and the concomitant non-expression of CK19 (12,14,15). Several reports document the close association of the CK19 expression level with de-differentiation processes of human hepatocytes (11,12). Notably, the loss of albumin production (16)(17)(18), as well as the down-regulation of cytochrome P450 isoenzymes was coupled with the induction of CK19 (19,20).…”

Section: Discussionmentioning

confidence: 99%

“…Cytokeratins represent specific differentiation markers. Stable expression of CK18 is typically seen in well-differentiated functionally active hepatocytes, whereas increasing CK18 level and de novo synthesis of CK7 and CK19 account for a de-differentiated phenotype (11,12). In this context, daily medium change evoked rapid CK18 up-regulation, and de novo synthesis of CK19, reaching a plateau phase after 10 and 15 days, respectively.…”

Section: Analysis Of Asgpr Expression Levelmentioning

confidence: 99%

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Autocrine stimulation of human hepatocytes triggers late DNA synthesis and stabilizes long-term differentiation in vitro

Leckel

Strey²,

Bechstein³

et al. 2008

Int J Mol Med

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Abstract. Isolated human hepatocytes are of great value in investigating cell transplantation, liver physiology, pathology, and drug metabolism. Though hepatocytes possess a tremendous proliferative capacity in vivo, their ability to grow in culture is severely limited. We postulated that repeated medium change, common to most in vitro systems, may prevent long-term maintenance of hepato-specific functions and growth capacity. To verify our hypotheses we compared the DNA synthesis and differentiation status of isolated human hepatocytes, cultured in medium which was renewed every day or was not changed for 3 weeks ('autocrine' setting). Daily medium change led to rapid hepatocellular de-differentiation without any signs of DNA replication. In contrast, the autocrine setting allowed hepatocytes to become highly differentiated, demonstrated by an elevated ASGPr expression level, and increased albumin and fibrinogen synthesis and release. Cytokeratin 18 filaments were stably expressed, whereas cytokeratin 19 remained undetectable. Hepatocytes growing in an autocrine fashion were activated in the presence of hepatocyte growth factor (HGF), evidenced by c-Met phosphorylation. However, HGF response was not achieved when the culture medium was renewed daily. Furthermore, the autocrine setting evoked a late but strong interleukin 6 release into the culture supernatant, reaching maximum values after a 10-day cultivation period, and intense BrdU incorporation after a further 5-day period. Our data suggest that preservation of the same medium creates environmental conditions which allow hepatocytes to control their differentiation status and DNA synthesis in an autocrine fashion. Further studies are necessary to identify the key mediators involved in autocrine communication and to design the optimal culture configuration for clinical application.

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“…In vitro studies provided direct proof of a lineage generation and hepatocytic differentiation capacity of precursor ("oval") cells and identified environmental factors that may be important for the hepatocytic differentiation from precursor cells [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Neoductular progenitor cells regenerate hepatocytes in severely damaged liver: a comparative ultrastructural study

Mandache¹,

Vidulescu²,

Gherghiceanu³

et al. 2002

J Cellular Molecular Medi

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In severely injured liver, stem cells give rise to progeny that tend to replace lost hepatocytes. Neoductular reaction appears as an inherent stage of liver reconstruction following severe damage caused by different pathological mechanisms. Few ultrastructural types of progenitor cells have been described, and some molecular phenotypes of progenitor stages have been characterized, but the details of the differentiation process are largely unknown. We prepared for light and electron microscopy examination human liver from biopsies of patients with chronic active hepatitis, and rat liver with allyl alcohol‐induced periportal necrosis. We found that progenitor neoductular cells acquire the hepatocytic polarity pattern during a multi‐step process apparently involving cell migration and dissolution of neoductular basement membrane. An intermediate stage with “mixed” ductular and hepatocytic polarity was described.

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Dedifferentiation of human hepatocytes by extracellular matrix proteins in vitro: quantitative and qualitative investigation of cytokeratin 7, 8, 18, 19 and vimentin filaments

Cited by 46 publications

References 43 publications

Localization of candidate stem and progenitor cell markers within the human cornea, limbus, and bulbar conjunctiva in vivo and in cell culture

Localization of candidate stem and progenitor cell markers within the human cornea, limbus, and bulbar conjunctiva in vivo and in cell culture

Autocrine stimulation of human hepatocytes triggers late DNA synthesis and stabilizes long-term differentiation in vitro

Neoductular progenitor cells regenerate hepatocytes in severely damaged liver: a comparative ultrastructural study

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