Elsevier

Hepatology Research

Volume 25, Issue 2, February 2003, Pages 149-157
Hepatology Research

Expression of progenitor cell markers in livers with fulminant massive necrosis

https://doi.org/10.1016/S1386-6346(02)00205-XGet rights and content

Abstract

Studies of stem cells in various organs have greatly progressed, and progenitor cells have been confirmed even in liver by recognition of cytokeratin 14 (CK14), c-kit, flt-3, and CD34. We, therefore, immunohistochemically examined the expression of these progenitor cell markers in patients with confluent or massive necrosis, in addition to CK19, albumin, vimentin, and Ki-67. Our subjects were six survivors and 14 deceased patients. Expression of CK14 and c-kit was found in a small number of cells lining biliary ductule-like structures, and that of flt-3 was found in many lining cells in two deceased patients with multi-lobular necrosis. CK14 positive cells were positive for c-kit, flt-3, and CK19 in semi-serial sections, but were negative for albumin, Ki-67, and CD34. In conclusion, expression of CK14 and c-kit was found in a small number of cells lining biliary ductule-like structures, and that of flt-3 was found in many cells lining biliary ductule-like structures. CK14-positive cells were positive for c-kit, but negative for CD34. Since c-kit is a hematopoietic marker, our study suggests that CK14- and c-kit-positive cells may be derived from bone marrow in liver with fulminant hepatitis.

Introduction

Stem cells are generally responsible for normal tissue renewal during regeneration following injury [1], [2]. Hepatocytes usually repair hepatic necrosis by mitosis, but if their division is inhibited, oval cells that are thought to develop into hepatocytes and biliary epithelial cells can proliferate [2], [3], [4]. It has recently been reported that the stem cells in bone marrow develop into hematopoietic and mesenchymal lineages in addition to hepatic progenitor cells, oval cells, hepatocytes, or biliary epithelial cells [1], [5], [6], [7], [8], [9], [10], [11], [12]. The oval cells are thought to be progenitor cells in the liver. Moreover, cells positive for cytokeratin 14 (CK14) have recently been reported also to be progenitor cells and are thought to belong to a member of stem cells [13], [14]. The consensus definition of stem cells is likely to include at least three ideas [5]: stem cells are able to reproduce themselves, they are able to give rise to differentiated cells, and they are also thought to undergo obligatory asymmetric division to yield one stem cell daughter and one daughter destined to differentiate. Significant contribution of stem cells to the regenerative process occurs only under circumstances in which residual differentiated cells are functionally compromised and/or cannot proliferate.

Since it is of great interest to test for the presence of CK14- [10], [11], [13], [14], CD34- [8], [9], vimentin- [13], [15], [16], c-kit- [6], [8], [9], [17], [18], [19], [20], [21], or flt-3- [19], [20] positive cells in hepatic regeneration, we immunohistochemically examined expression of these progenitor cell markers in patients with fulminant massive or confluent necrosis.

Section snippets

Patients and methods

We examined 20 patients with confluent or massive hepatic necrosis. Fourteen of them died of hepatic failure, while the remaining six have survived hepatic failure. All six survivors underwent liver biopsy by Silverman's needle under laparoscopy when they recovered from hepatic failure, and the 14 deceased patients underwent autopsy within 6 h after death. The clinical data on these patients are summarized in Table 1. The patients included 11 women and nine men, ranging in age from 19 to 74

Results

The causative agent of confluent or multi-lobular (massive) necrosis was hepatitis B virus (HBV) infection, drugs or excessive consumption of alcohol (Table 1). The 14 deceased patients were diagnosed as fulminant hepatitis. Three of them were diagnosed as acute type of fulminant hepatitis, and the mean number of days from onset to diagnosis was 5.7. The remaining 11 patients were diagnosed as subacute type of fulminant hepatitis, and the mean number of days from onset to diagnosis was 20.5.

Discussion

Recent reports have surprisingly suggested that tissue-specific adult stem cells have the potential to contribute to replenishment of multiple adult tissues [1], [2], [3], [4], [5]. Although studies of liver regeneration have progressed [1], [2], [3], [4], [10], the stem cells, primordial cells, and progenitor cells, including oval cells, in adult human liver have not been thoroughly elucidated [2], [5], [11], [12]. Recently, CK14, CD34, c-kit, and flt-3 have been recognized to be markers of

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