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发表于 2009-3-5 00:03 |只看该作者 |倒序浏览 |打印

作者：Maggie H. Walkup, David A. Gerber作者单位：Department of Surgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
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      【摘要】* D* G4 B' j9 }6 L
   The field of stem cell biology has exploded with the study of a wide range of cellular populations involving endodermal, mesenchymal, and ectodermal organs. One area of extensive study has included the identification of hepatic stem and progenitor cell subpopulations. Liver stem cells provide insights into the potential pathways involving liver regeneration that are independent of mature hepatocytes. Hepatic progenitor cells are either bipotent or multipotent and capable of multiple rounds of replication. They have been identified in fetal as well as adult liver. Various injury models have been used to expand this cellular compartment. The nomenclature, origin, and function of the hepatic progenitor cell populations are areas of ongoing debate. In this review, we will discuss the different definitions and functions of hepatic progenitor cells as well as the current research efforts examining their therapeutic potential. , O/ c% a! I( d4 t  K6 k
      【关键词】 Stem cell Progenitor cell Oval cell Liver regeneration; e) ]5 E* x! Q5 [0 M0 J. K
   INTRODUCTION8 m* }. u  z! t6 K2 C, @" [( d% J2 d
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It has been suggested that when the regenerative ability of mature hepatocytes is insufficient, then the capacity of the liver for innate cellular recovery occurs secondary to a separate and unique population of liver cells. The origin, nomenclature, and function of these cells have been a longstanding area of study and debate. Hepatic progenitor cells have been broadly characterized as a wide range of cell populations by multiple scientific teams. These cells have been investigated from the very early embryonic stages through adulthood, using a diverse range of experimental models.4 x8 M7 ^& L' U" s! [3 d

A stem cell is typically characterized by its capacity for self-renewal and ability to give rise to multiple differentiated cellular populations (often termed cellular plasticity)  stem cells are routinely characterized by the absence rather than the presence of specific lineage-related markers.
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LIVER STEM CELL POPULATIONS5 |( Z5 ~1 Y5 h5 G) A9 w; Q
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The vast majority of liver-related stem cell research has focused on either fetal-derived hepatic stem cells or oval cells. The oval cell is typically defined as a unique cellular population that is generated from the biliary compartment in response to hepatic injury . The nomenclature and function of described liver-related stem cell populations, including the progenitor cell populations, remains an area of dispute, as the majority of these cellular populations have not been used in a therapeutic approach to provide organ-associated function. To further complicate the challenge with nomenclature, adult liver stem cells are often referred to as hepatic progenitor cells, hepatic oval cells, or both.

For the purposes of this review, we will characterize hepatic progenitor cells as either somatic hepatic progenitor cells (those cells that can be isolated from adult liver without chemical insult or partial hepatectomy), fetal hepatic progenitor cells (due to their origin and isolation from within the developing liver bud), or the previously characterized oval cell. The role of oval cells in liver regeneration and their potential as hepatic progenitors will be discussed in further detail. With the varying descriptions of unique hepatic progenitor cell populations, it is possible that overlap exists among differing populations.

There is currently a dichotomy between our understanding of the processes involved in stem cell differentiation and organ development compared with the unanswered questions relating to the postnatal role of stem or progenitor cell populations as they persist into adulthood. Are the latter groups undifferentiated stem cell populations that persist beyond the fetal period or are they de novo stem cells generated by signals from the adult somatic cellular compartment? Further comprehension of characterization and the process by which select stem or progenitor cells undergo differentiation will provide greater insight into tissue development and organogenesis . This understanding could also play a role in developing alternative cell therapy strategies. This review focuses on multiple liver-derived stem or progenitor cell populations that have been isolated from liver tissue at various stages of development or in response to select injury models.

FETAL LIVER

The cellular plasticity associated with various fetal tissues makes embryonic development an ideal place to search for stem/progenitor cell populations. During embryogenesis, the liver arises from the gut tube as an out-pouching, referred to as the liver bud. The liver bud begins to grow and differentiate, and subsequent cellular contact with the cardiac mesoderm and the production of fibroblast growth factors (FGFs) in the local environment induces the endoderm toward hepatic development .

As the liver bud grows, the cellular constituent of the liver is composed of hepatoblasts. Hepatoblasts are defined as the precursors for hepatocytes as well as for cholangiocytes, the cells that form the biliary ductal system of the liver .

Investigators studying the characterization of the stem cell compartment in the fetal liver have focused on defining markers associated with stem cells as well as those associated with hepatic cells and then identifying which cells possess a combination of the markers. Petersen et al. demonstrated Thy-1, a marker of hematopoietic stem cells, .

The origin of the fetal hepatic stem cell populations has been a controversial topic. Early in development the fetal liver is the major location of hematopoiesis . Further work with labeling techniques will help us gain understanding into the migration and differentiation of the progenitor cells.8 c1 U, [6 l# c5 T
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ADULT-DERIVED HEPATIC PROGENITOR CELL POPULATIONS

Our group has isolated a hepatic progenitor cell population from adult murine liver without a preceding injury to the liver .

Figure 1. Hepatic progenitor cell colony isolated from murine adult liver tissue. (A): Day 4 culture demonstrating a small colony; original magnification, x200. (B): Day 19 of culture demonstrating cellular proliferation and colony expansion; original magnification, x100.4 M  j7 E; h! M  j" F  A

Other groups have described novel methods for isolating progenitor cell populations, including isolating them under hypoxic conditions while simultaneously inducing cell aggregate formation .

Although the potential for many of these adult-derived progenitor cells is promising, there is still a tremendous amount of investigation to be done before their therapeutic potential can be realized. Perhaps most significantly, there is an ongoing challenge with respect to identifying unique markers that will support the isolation and purification of these cells from the mature hepatocyte and nonparenchymal cell populations within the liver.

The issue of dedifferentiation as a process that generates stem cell populations has been debated in recent years. Tateno et al. demonstrated that hepatocytes in culture expressed biliary markers .
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CELL RESPONSES IN INJURY MODELS

Since the identification and subsequent isolation of progenitor cells is a challenge in uninjured livers, several groups have developed experimental models of liver injury to activate and augment specific cell populations. Just as there are several models for inducing liver injury, there are several theories as to which cell population is responsible for regenerating the lost or damaged liver parenchyma.8 L7 Q/ Z& n% t
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The typical response to a cellular vacuum secondary to a chemical or surgical insult within the liver involves replication of adult hepatocytes. Investigators have shown that mature hepatocytes can undergo 8 to 12 rounds of cellular division in response to consecutive partial hepatectomies .5 V4 @# ]' v0 b/ U2 Q9 {

The oval cell, located in the terminal bile ducts, is a potential liver progenitor cell .( w8 v6 o% e) B

In response to 2-AAF injury, oval cells form new ductular structures that are extensions of the canals of Hering and are surrounded by a continuous basement membrane. They attach at their distal end to a hepatocyte .5 \6 U  ]& Q. ~4 C; g+ s0 F
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Much like the controversy surrounding the origin of fetal liver stem cells, there has been some inquiry into the possibility that oval cells do not originate from the liver but instead are activated bone marrow stem cells that migrate to the liver in response to injury. This hypothesis was based in part by the fact that oval cells can express certain bone marrow stem cell markers, such as c-kit . These studies show only a minor cellular contribution with respect to liver repopulation.
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Another model of liver injury involves retrorsine treatment followed by partial hepatectomy .  l) \7 j: ]! E9 C

Figure 2. Small hepatocyte-like progenitor cells are seen in a small cluster located in the liver after retrorsine treatment and partial hepatectomy. (A): Day 6 after partial hepatectomy demonstrates a small cluster of cells. (B): Day 14 after partial hepatectomy there is expansion of the cell population within the parenchyma of the liver. H&E staining; original magnification, x200. Images courtesy of William B. Coleman, Ph.D.: ^6 n8 E. e* e
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Gordon et al. also explored the therapeutic potential of these small hepatocyte-like progenitor cells through transplantation .1 c. D2 S4 S9 [

A majority of the research involving oval cells has been in rat models. However, recent experiments using a retrorsine/partial hepatectomy injury model in mice demonstrated proliferation of a liver progenitor cell compartment. After subjecting mice to retrorsine and partial hepatectomy, the authors found a population of cells that expressed the hematopoietic stem cell markers c-kit and Thy-1. In vitro, this same population of cells differentiated into cells expressing either biliary markers (e.g., CK-19) or hepatic markers (e.g., albumin) .7 l, D5 h$ Q; h( B, j6 ?

Investigators have also focused on identifying bipotent cells in the human liver. Baumann et al. used immunohistochemistry to study human livers in fulminant hepatic failure. They found upregulation of a population of cells that expressed c-kit . Although this is a promising beginning, the investigation involving human liver progenitor cells is in its nascent stages, and much remains to be learned. Figure 3 is a summation of select cellular populations along with their identifying characteristics.

Figure 3. Schematic outlining the differentiation and commitment of the hepatic-related cells from their early stages in development through adulthood. Abbreviations: -FP, -fetoprotein; AFP, -fetoprotein; Alb, albumin; ALB, albumin; CK, cytokeratin; G6P, glucose-6-phosphatase; ICAM, intercellular adhesion molecule.

LIVER STEM CELLS AND TRANSPLANTATION
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Although the ultimate application using hepatic/stem progenitor cells involves the development of an alternative therapy to liver transplantation for patients with liver failure, the prospect of this clinical reality remains in the future. There are currently more than 17,000 people on the waiting list for a liver transplant, with the majority of these patients suffering with cirrhosis, a manifestation of chronic liver injury (http://www.unos.org). In 2005, only approximately one-third of people waiting for a liver actually underwent a transplant  involves the necessity to transplant large numbers of cells to achieve acceptable function, as well as providing an outlet for biliary excretion.* ?- U$ v7 m( [
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Several studies have looked at the potential of stem/progenitor cells in transplantation , and one of the clinical challenges includes engraftment of functional transplanted cells.

A concern about using hepatic progenitor cells for therapeutic transplantation is the link between oval cells and hepatocellular carcinoma. An antigenic relationship between oval cells and hepatocellular carcinoma has been previously demonstrated. In the 1970s and 1980s, the oval cell was studied for its malignant potential . However, no definitive link between adult or fetal hepatic progenitor cells and carcinoma has been clearly demonstrated. Perhaps this population of cells will not have the same carcinogenic potential, but this is certainly an area of research that will require further exploration.

Bioartificial liver (BAL) systems attempt to provide supportive function for a patient with liver disease while addressing the issue of malignant potential and immunologic reaction by creating a barrier between the functioning hepatocytes and the patient. This field has been extensively studied over the past few decades, with several studies reaching preclinical trials as investigators have analyzed BAL design and cell source . Many of these issues, such as cellular viability and xenografts, may be dealt with by using species-specific stem cells.1 s6 `/ D) n- H2 n0 G" m0 X# `
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SUMMARY: _, @5 K8 g( s% p( X

In summary, the field of hepatic stem cell study has undergone tremendous growth during the past decade. The initial phase of this research has focused on isolating and characterizing select cellular populations, a critical first step. It is anticipated that over the next few years we will see an in-depth investigation of the hepatic stem/progenitor cell populations with respect to differentiation signals. A balance must be achieved between developing a critical mass of functional cells while controlling the regenerative capacity of the progenitor cells . Further exploration into methods of transplantation and engraftment of these cells will be required. As we move forward in the field of hepatic progenitor cell research, these hurdles must be overcome for cell transplantation involving stem/progenitor cells to become a therapeutic possibility.

DISCLOSURES/ l% A7 Q* r) f7 \
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The authors indicate no potential conflicts of interest.
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ACKNOWLEDGMENTS& I! \) i  V1 I- ]

This work was supported by NIH Grant T32-GM008450 (M.H.W.) and NIH Grant 5K08DK59302 (D.A.G.). We thank Dr. Bill Coleman for supplying images of small hepatocyte-like progenitor cells.& {9 W* X  V' J6 x$ ^5 |) q- {( ~
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