The aim of this study was to detect donor-derived hepatocytes and gastrointestinal epithelial cells in recipients of sex-mismatched allogeneic hematopoietic cell transplants, and to assess the effect of tissue injury on the extent of the repopulation. A total of 29 paraffin-embedded biopsy samples were reviewed. Double labeling by immunohistochemistry and fluorescence in situ hybridization was performed. Eighty-nine percent of sex-mismatched samples with histologic evidence of injury demonstrated the presence of donor-derived hepatocytes and gastrointestinal epithelial cells (mean 2.4%). None of the hepatocytes and gastrointestinal epithelial cells in samples obtained from female recipients with female donors showed a Y chromosome signal. The proportion of donor-derived hepatocyte and gastrointestinal epithelial cells in samples with severe graft-versus-host disease was greater than that of samples with mild/moderate graft-versus-host disease (P=0.09). No relationship between the source of stem cells and the population rate was detected (P>0.05). We conclude that some recipient hepatocytes and gastrointestinal tract epithelial cells are replaced by donor-derived cells during tissue injury. The severity of tissue injury seems to influence on the extent of this repopulation.
Every tissue possesses stem cells that enable self renewal.1, 2, 3 To sustain homeostasis, stem cells regulate the rate of cell production by increasing the function of cells undergoing cellular proliferation and maturation in response to tissue injury.1, 2, 3, 4, 5, 6 Recent reports suggest that hematopoietic stem cells have a capacity to transdifferentiate.1, 2, 6, 7, 8, 9, 10
Allogeneic hematopoietic stem cell transplantation (alloHCT) has become standard treatment for several diseases.11 Current estimates of annual numbers of alloHCT are 12 000–15 000 worldwide, and transplant-related mortality in the first year after alloHCT averages 30%.12 Graft-versus-host disease (GVHD), either acute (aGVHD) or chronic (cGVHD), is a major complication and contributes to transplant-related morbidity and mortality.12, 13, 14 aGVHD occurs in approximately 40–60% of HLA-identical sibling transplants and cGVHD develops in around 50–60% of transplants.12, 13, 14 Both acute and chronic GVHD affect the skin, liver and gut.12, 13, 14 Since histological findings of GVHD are nonspecific, diagnosis often requires both clinical and histological criteria.12, 13, 14 The induction of increased histocompatibility antigens and leukocyte adhesion molecule expression on tissues such as bile ducts, gastrointestinal mucosa and epidermis identifies these cells as targets for alloreactive donor T cells. Such T cells proliferate and secrete inflammatory cytokines (IL-2, IL-1 and TNF-α which induce tissue injury.13, 15, 16
Bone marrow (BM)-derived stem cells have been shown to engraft and populate hematopoietic as well as nonhematopoietic tissues during injury and repair. However, the contribution of BM cells to the generation of new hepatocytes and gastrointestinal epithelial cells and the role of the severity of the tissue injury on such responses are controversial. The aims of this study were to investigate the presence of donor-derived hepatocytes and gastrointestinal epithelial cells in sex-mismatched individuals following alloHCT, and to evaluate the effect of tissue injury, occurring as a result of the conditioning regimen or GVHD on the extent of the repopulation.
Materials and methods
A total of 29 paraffin-embedded liver (n:17) and gastrointestinal (n:12) biopsy samples of 28 recipients (male/female ratio: 16/12; median age: 31.0 years, range: 14–53 years) were investigated. All 28 individuals received alloHCT from their HLA-identical siblings at the Ankara University School of Medicine, Stem Cell Transplantation Unit. The median donor age was 30.0 years (range: 15–56 years). Sixteen of the 28 recipients had an ABO-mismatched donor. The source of the stem cells was peripheral blood (PB) in 21 and BM in seven recipients. Twenty-two recipients were conditioned with an ablative regimen consisting of busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). The remaining six received fludarabine-based reduced-intensity chemotherapy. All received short-term methotrexate and cyclosporine (Cs-A) (myeloablative) or mycophenolate mofetil and Cs-A (reduced intensity) to prevent GVHD after alloHCT. The hematologic and demographic characteristics of the recipients and donors are shown in Table 1a and b.
A liver biopsy was performed when liver injury tests and cholestatic liver enzymes were found to be increased. Gastrointestinal mucosal biopsies were performed to identify the etiological cause of nausea, vomiting, abdominal discomfort, inability to eat and diarrhea. No sequential liver and gastrointestinal tract biopsies were performed. Paraffin sections were stained by hematoxylin–eosin (HE). The diastase-digested periodic acid-Schiff and Masson's trichrome stains were utilized to enable a more extensive histopathological evaluation of the changes in the liver especially in terms of the bile duct damage and tissue fibrosis. Only HE-stained paraffin sections of the gastrointestinal tract biopsies were examined.
Diagnosis of the liver tissue injury
Conditioning regimen-related drug hepatotoxicity
Conditioning regimen-related hepatotoxicity was defined as an elevation of aminotransferases levels (greater than 1.3 times the upper limit of normal) occurring with an increase in the serum bilirubin level above the upper limit of normal, with or without an elevation of the level of cholestatic enzymes occurring from day −7 to +30 post-alloHCT screening.17 Serum alanine aminotransferase (ALT, normal: 10–37 IU/l), aspartate aminotransferase (AST, normal: 10–37 IU/l), gamma glutamyl transpeptidase, alkaline phosphatase and bilirubin levels were determined at days −7, −3, 0 and at days 1, 3, 7, 14, 21 and 30 post transplantation.
GVHD occurring in the liver
Hepatic GVHD was defined as an elevation of serum alkaline phosphatase levels (greater than two times the upper limit of normal) occurring in association with an increase in the serum bilirubin level above the upper limit of normal, with or without an increase in the serum aminotransferases levels at day +100 post-alloHCT. In each case, the diagnosis of hepatic GVHD occurring in the liver was confirmed by liver biopsy. The histologic criteria utilized were the finding of bile duct damage and/or ductopenia with infiltration of the smaller bile ducts with lymphocytes, portal area expansion with both lymphocytes and plasma cells and cholestasis as previously published.18
The limited/extensive GVHD classification was used for the clinical and histological grading of cGVHD of the liver. For histopathological grading, a modified scheme introduced by Shulman et al.19 was applied. The modified-histopathological GVHD grading scheme is shown in Table 2. Based on the total score, liver biopsy samples were divided into two distinct groups. Samples with histopathological GVHD grading of less than 6 were considered as mild/moderate GVHD of the liver. Scores between 6 and 10 were considered as severe GVHD.
GVHD of the gastrointestinal tract
Gastrointestinal tract biopsy was performed in endoscopically abnormal areas of the gastrointestinal tract. Gastrointestinal biopsies were stained with HE, and graded for the presence and severity of GVHD using the criteria of McDonald et al.20 For statistical analysis, grades were sorted into two groups according to the severity of the epithelial damage. Grades I--II, consisting of prominent inflammatory reaction and mild epithelial damage, were grouped as ‘mild GVHD’. Grade III and IV changes with severe epithelial damage, consisting of drop out of crypts, and denudation of epithelial cells were grouped as ‘severe GVHD’.
Sections (4 μm) of formalin-fixed paraffin-embedded tissues were immunostained using monoclonal mouse anti-human hepatocyte antibody (Clone OCH1E5, DAKO, Glostrup, Denmark) at a 1:30 dilution to identify hepatocyte and anti-human cytokeratin 7 (Clone K72.7, DBS CA, USA,) and at a 1/100 dilution to identify bile duct epithelial cells. Anti-human cytokeratin (Novacastra, UK, clone: 5D3+LP34) at a 1:50 dilution was used to demonstrate gastrointestinal epithelial cells, and a mixture of anti-CD45 at a 1:20 dilution (Novacastra, UK, clone: RP2/18+RP2/22) and anti-CD15 at a 1:50 dilution (Neomarkers, USA, clone 15CO2) was used to identify lymphocytes and leukocytes. These primary antibodies were incubated for 60 min at room temperature on two separate sections for which HRP-conjugated goat anti-mouse secondary antibody followed by DAB substrate for light microscopic visualization of the cells was used.
In situ hybridization
The immunostained sections were prepared for fluorescence in situ hybridization (FISH) by sequential acid incubation, denaturation, and proteinase K digestion steps. After formamide denaturation and formalin fixation, the slides were dehydrated in graded ethyl alcohols and air dried. FISH was performed on pretreated slides using spectrum orange-labeled DXZ1 (Xp11, X-q11.1) (CEPX) Alpha Satellite and spectrum green-labeled DYZ1 (Y) (Yq1 2) probes (Vysis Inc., Downers Grove, IL-USA) for labeling X and Y chromosomes. After the application of probes, covered and sealed slides were denatured 10 min at 90°C and hybridized 12–18 h at 42°C using a hybrid incubation chamber (Vysis Inc., Downers Grove, IL, USA). DAPI was performed for nuclear counter-staining (Vysis Inc., Downers Grove, IL, USA).
The slides were viewed and analyzed systematically using an image analyzer system (Olympus microscope with 3X61 motorized, Cyto-Vision, Applied Imaging). Every field was z-scanned at seven levels in order to eliminate misinterpretation due to any super- or juxta-position of the cells on dark field for X and Y chromosomal signals. Only the cells with two nuclear spots were considered for interpretation. At the same time, immunophenotypes of either hepatocytes or ductal cells for liver biopsies, and mucosal epithelial cells and inflammatory cells on GI biopsy sections were assessed on bright field for confirmation of the cell type. The percentage of donor type chimerism was calculated by counting 250 cells on each section. All available ductal cells in each liver biopsy were counted.
The data were analyzed using the Student's t-test and χ2 test. A P-value of less than 0.05 was considered significant.
Among 29 biopsy samples, 27 were sex-mismatched biopsy samples and two were sex-matched biopsy samples (female to female), which were used as control. Sixteen of the 27 sex-mismatched samples were obtained from male recipients who had female donors and 11 were obtained from female recipients who had male donors. Among 27 sex-mismatched biopsy samples, 16 were liver and 11 were gastrointestinal tract (three antrum of stomach, six duodenum and two rectum). One recipient with a sex-mismatched donor had both a liver and a gastrointestinal biopsy. Ten of the 12 female recipients had no prior history of male pregnancy. None of the biopsies had had normal tissue. However, the extent of tissue injury was variable.
Donor-derived hepatocyte and gastrointestinal cell in AlloHCT recipients
The mean time from transplantation to biopsy was 5.9 months (range: 1–20 months). Twenty-four of the 27 sex-mismatched samples (88.9%) demonstrated donor-derived hepatocyte and gastrointestinal epithelial cell repopulation with a mean of 2.4% (range: 0.8–6.4%).
The mean time from transplantation to biopsy was 8.2 months (range: 3–20 months). Fifteen of these 16 sex-mismatched samples (93.8%) demonstrated donor-derived hepatocyte repopulation (DDHR) with a mean of 2.4% (range: 0.8–5.6%) of the hepatocytes being of donor origin (Figure 1a and b). DDHR was not demonstrated in the remaining one sex-mismatched sample; however, donor-derived unspecified sinusoidal cells were seen in the liver sinusoids of this individual. None of the hepatocytes of sex-matched liver biopsy samples obtained from female recipients with female donors manifested a Y chromosome signal.
Donor gender did not influence the presence or proportion of DDHR. Three of the four samples obtained from female recipients with male donors demonstrated DDHR with a mean proportion of 1.2% of the hepatocytes (range: 0.8–1.6%) (Table 3), while all of the 12 samples obtained from male recipients with a female donor demonstrated DDHR with a mean proportion of 2.7% of the hepatocytes (range: 0.8–5.6%) (1.2 vs 2.7%, P>0.05).
Bile duct epithelial cells
Eight of the 17 sex-mismatched liver biopsy samples had available portal areas with recognizable bile ducts. Two to six portal areas were available for each of these samples. A total of 136 bile duct epithelial cells (mean: 19.4 epithelial cells per sample; range: 4–36 epithelial cells/sample) were counted. None of the bile duct epithelial cells expressed a different nuclear signal from that of the recipient.
Gastrointestinal tract epithelial cell
The mean time from transplantation to biopsy was 2.5 months (range: 1–7 months). Nine of the 11 sex-mismatched gastrointestinal biopsy samples (81.8%) demonstrated donor-derived gastrointestinal tract epithelial cell repopulation (DDGECR) with a mean of 2.5% (range: 0.8–6.4%) (Figure 2a and b). The remaining two sex-mismatched samples did not demonstrate DDGECR, but donor-derived inflammatory cells were present in the biopsies. Furthermore, none of the gastrointestinal epithelial cell of sex-matched biopsy samples obtained from female recipients with female donors manifested a Y chromosome signal.
Donor gender did not influence either the presence or proportion of DDGECR. Six of the seven sex-mismatched samples obtained from female recipients with a male donor demonstrated DDGECR with a mean proportion of 2.3% (range: 0.8–6.4%) (Table 3), whereas three of the four samples obtained from male recipients with a female donor demonstrated DDGECR with a mean proportion of 2.8% (range: 2.0–3.2%) (2.3 vs 2.8%, P>0.05).
Tissue injury and donor-derived cell repopulation
Eight of the 16 recipients with sex-mismatched donors had shown drug-related liver toxicity during the first month after alloHCT. Serum AST and ALT levels increased significantly (serum AST level from 30.3±16.1 to 55.9±35.3 IU/l at day 0 to 43.8±19.4 IU/l at day +7; serum ALT level from 31.3±13.8 to 65.6±41.3 IU/l at day 0 to 129.4±49.8 IU/l at day +7) (baseline ALT vs day +7 ALT, P=0.0001). The mean time from onset of liver function test abnormalities to liver biopsy was 2.7 months (range: 1 day–12 months). The time from liver function test abnormalities to liver biopsy did not influence either the presence or proportion of DDHR (P>0.05).
Ten of the 11 sex-mismatched gastrointestinal biopsy samples were identified as having acute GVHD. Five were graded as mild GVHD and five were graded as severe GVHD. The remaining one was diagnosed as mucositis. The proportion of DDGECR in samples with severe GVHD of the gastrointestinal tract was slightly higher than that of samples with mild GVHD of the gastrointestinal tract (mean proportion 3.1% (range: 0.8–6.4%) vs 1.1% (range: 0–2.8%), P=0.09) (Table 3, Figure 3). All five gastrointestinal samples with severe GVHD demonstrated DDGECR, whereas three of the five gastrointestinal samples with mild GVHD demonstrated DDGECR (5/5 vs 3/5, P>0.05) (Table 3).
With histopathological GVHD grading of the liver, 10 of the 16 sex-mismatched liver biopsy samples were graded as mild/moderate GVHD, whereas the remaining six samples were graded as severe GVHD. DDHR in samples with severe GVHD of the liver were slightly more common than that of samples with mild/moderate GVHD of the liver (6/6, 3.0% vs 9/10, 1.7%, respectively; P=0.09) (Table 3, Figure 3).
With clinical GVHD grading, seven of the 16 recipients with sex-mismatched donors had limited cGVHD. The remaining nine had extensive cGVHD. There was no significant difference in terms of the presence or proportion of DDHR between liver biopsy samples with limited and extensive cGVHD (2.4% (range: 0–5.6%) vs 2.1% (range 0.8–4.2%), P>0.05). Six of the seven samples with limited cGVHD demonstrated DDHR, whereas all of the nine samples with extensive cGVHD demonstrated DDHR (Table 3).
The type of conditioning regimen did not influence either the presence or proportion of DDHR. The presence or proportion of DDHR showed no significant difference in individuals with hepatic GVHD with/without conditioning regimen-related drug hepatotoxicity (8/8, mean proportion, 2.1% vs 7/8 mean proportion, 2.4%; P>0.05) (Table 3).
Stem cell source
The source of the stem cells used for transplantation had no effect on the repopulation rate (P>0.05). Nineteen of the 21 tissue samples obtained from PB recipients demonstrated donor-derived hepatocyte and gastrointestinal epithelial cell repopulation, while five of the six tissue samples obtained from BM recipients demonstrated donor-derived hepatocyte and gastrointestinal epithelial cell repopulation (mean proportion 2.7% (0.8–6.4%) vs 1.4% (0.8–2.0%), P>0.05) (Table 3).
In the present study, 89% of the sex-mismatched tissue samples demonstrated donor-derived hepatocyte and gastrointestinal epithelial cell repopulation with a mean proportion of 2.4%. Among these samples, DDHR was observed in 94% of the liver biopsy samples with a mean proportion of 2.4%. DDGECR was observed in 82% of the gastrointestinal biopsy samples with a mean proportion of 2.5%. This is the first study including a large number of cases (sample number: 29) demonstrating donor-derived hepatocyte and gastrointestinal epithelial cell repopulation when compared to the previous reports by Theise et al. (sample number: 6) and Korbling et al. (sample number: 12).1, 7 Donor gender did not influence the presence or proportion of donor-derived hepatocyte and gastrointestinal epithelial cell repopulation (for hepatocytes, mean proportion male to female, 1.2% vs female to male, 2.7%; for gastrointestinal epithelial cell repopulation, mean proportion male to female, 2.3% vs female to male, 2.8%, respectively; P>0.05). These data suggest that donor-derived hepatocyte and gastrointestinal epithelial cell repopulation occurs in alloHCT independent of donor gender.
Several studies have addressed the question of the extent of donor-derived hepatocyte and gastrointestinal epithelial cell repopulation.1, 2, 3, 4, 7, 21, 22 In the present study, no relationship between tissue injury due to either conditioning regimen or the extent of GVHD and the presence and proportion of donor-derived hepatocyte and gastrointestinal epithelial cell repopulation was observed, although the proportion of donor-derived hepatocyte and gastrointestinal epithelial cell repopulation in individuals with severe GVHD was slightly greater. Kanazawa et al.23 and Korbling et al.7 reported that the frequency of DDHR in recipients is unrelated to liver injury in both experimental models and humans. In contrast, Theise et al.1 reported that the extent of engraftment in sex-mismatched graft seems to correlate with the severity of tissue injury. When tissue injury was mild, a low level of stem cell repopulation occurred. On the other hand, with severe tissue injury, a higher level of stem cell repopulation occurred.1 We believe that these controversial findings may be the consequence of the nature of the injury, the length of the period between injury and biopsy, or the sensitivity of the techniques investigators have used.
The origin of these ‘repopulated cells’ and the manner in which they generate hepatocytes and gastrointestinal tract epithelial cells are controversial. Basic concepts on stem cell biology including plasticity, transdifferentiation and fusion have all been reported.1, 2, 5, 22, 23, 24, 25, 26, 27, 28, 29 Recent progresses in stem cell studies have indicated that certain mammalian cells maintain a high degree of plasticity for multilineage cell differentiation.25, 26 The plasticity is supported by the finding of intrahepatic chimerism in transplant recipients.25, 26 Theise et al. investigated the question of whether hepatocytes could be generated from the BM cells of the recipient.1 Alison et al.2 and Korbling et al.7 addressed this question in the liver of recipients with sex-mismatched donors and we made our own observations as well.30 In these studies, the frequency of BM-derived hepatocytes in the liver of the recipients ranged from 0.5 to 8% without using a correction factor. Two other studies of transplants were not able to detect BM-derived cells in the liver.31, 32 In the present study, in addition to being able to demonstrate donor-derived hepatocyte and gastrointestinal epithelial cell repopulation, such repopulation was found to be slightly greater in recipients of PB transplantation as compared to recipients of BMT (2.7 vs 1.4%, P=0.08). Based on the results of all of these studies, it appears that donor-derived hepatocyte and gastrointestinal epithelial cell repopulation occurs, but at a low frequency.
Cell fusion has been reported as an alternative mechanism responsible for cell fate changes.27, 28, 29 In vitro fusion between embryonic stem cells and somatic cells has been described27, 28, 29 but its frequency is low. Terada et al.29 were not able to demonstrate fusion in their hematopoietic stem cell (HSC) culture model. They have suggested that HSCs may be incapable of fusion.29 The frequency of in vivo fusion between transplanted marrow cells and injured liver in a model of tyrosinemia was higher than in other circumstances or models. These investigators have suggested that plasticity occurs first and is followed later by fusion.28 Unfortunately, the present work does not discriminate among the various potential mechanisms of cellular repopulation.
Although donor-derived hepatocyte and gastrointestinal tract epithelial cell repopulation was demonstrated in this study, we were unable to demonstrate cholangiocyte repopulation. This finding is in contrast with the data of other studies, which report cholangiocyte engraftment in all samples but at different proportions.1, 33 Our failure to demonstrate this phenomenon may be a result of the limited number of portal areas examined in the liver biopsy samples available in the present study.
Women who have not undergone transplantation can harbor a Y chromosome in their liver if they have had a previous male child pregnancy. This has been documented by several different investigators.34, 35 In the present study, 10 of the 12 recipients had no male child or abortion of a male gestational product. This observation supports that the Y-chromosome harboring hepatocytes in the female liver grafts in the present study originated from male donor-derived stem cells.
Based on the results of this study, we conclude that some hepatocytes and gastrointestinal tract epithelial cells of recipients with sex-mismatched donors are replaced by donor-derived stem cells. Such repopulation occurs at a low frequency. The severity of tissue injury seems to have a minimal effect on the proportion of donor-derived hepatocyte and gastrointestinal epithelial cell repopulation. We suggest that the origin of these repopulated cells in the post transplant period is donor-derived stem cells. The fate of the donor-derived hepatocyte and gastrointestinal epithelial cell repopulation can only be evaluated using systematically performed tissue biopsies in longitudinal studies.
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We thank Muhip Ozkan, MD, Ankara University Agriculture Faculty, Department of Biometry-Genetics, for his assistance with statistical analysis; Ajlan Tukun, MD, Ankara University School of Medicine, Department of Medical Genetics, for her generous help in using the image analyzer system; and Yasemin Sahin, Ankara University Biotechnology Institute, and Klara Dalva Ankara University School of Medicine, Hematology Laboratory, for their technical assistance. Ramazan Idilman and Mutlu Arat have been supported by the Turkish Academy of Sciences, in the framework of the Young Scientist Award Program (EA-TUBA-GEBIP/2001-1-1, 2004-1-1).
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Idilman, R., Kuzu, I., Erden, E. et al. Evaluation of the effect of transplant-related factors and tissue injury on donor-derived hepatocyte and gastrointestinal epithelial cell repopulation following hematopoietic cell transplantation. Bone Marrow Transplant 37, 199–206 (2006) doi:10.1038/sj.bmt.1705214
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