Hepatocytes and Epithelial Cells of Donor Origin in Recipients of Peripheral-Blood Stem Cells
Martin Körbling, M.D., Ruth L. Katz, M.D., Abha Khanna, M.A., Arnout C. Ruifrok, Ph.D., Gabriela Rondon, M.D., Maher Albitar, M.D., Richard E. Champlin, M.D., and Zeev Estrov, M.D.
Background Bone marrow contains stem cells with the potentialto differentiate into mature cells of various organs. We determinedwhether circulating stem cells have a similar potential.
Methods Biopsy specimens from the liver, gastrointestinal tract,and skin were obtained from 12 patients who had undergone transplantationof hematopoietic stem cells from peripheral blood (11 patients)or bone marrow (1 patient). Six female patients had receivedtransplants from a male donor. Five had received a sex-matchedtransplant, and one had received an autologous transplant. Hematopoieticstem-cell engraftment was verified by cytogenetic analysis orrestriction-fragment–length polymorphism analysis. Thebiopsies were studied for the presence of donor-derived epithelialcells or hepatocytes with the use of fluorescence in situ hybridizationof interphase nuclei and immunohistochemical staining for cytokeratin,CD45 (leukocyte common antigen), and a hepatocyte-specific antigen.
Results All six recipients of sex-mismatched transplants showedevidence of complete hematopoietic donor chimerism. XY-positiveepithelial cells or hepatocytes accounted for 0 to 7 percentof the cells in histologic sections of the biopsy specimens.These cells were detected in liver tissue as early as day 13and in skin tissue as late as day 354 after the transplantationof peripheral-blood stem cells. The presence of donor cellsin the biopsy specimens did not seem to depend on the intensityof tissue damage induced by graft-versus-host disease.
Conclusions Circulating stem cells can differentiate into maturehepatocytes and epithelial cells of the skin and gastrointestinaltract.
Pluripotent bone marrow stem cells have the capacity for self-renewaland can differentiate into hematopoietic or mesenchymal1 celllineages. Studies in laboratory animals and humans indicatethat bone marrow stem cells can give rise to hepatic oval cells,hepatocytes, cholangiocytes,2,3,4 skeletal-muscle cells,5,6astrocytes, and neurons.7,8,9 To investigate whether such progenitorcells circulate in the blood, we studied biopsy specimens ofskin, liver, and gastrointestinal tract from recipients of peripheral-bloodstem cells from HLA-matched, sex-mismatched siblings for thepresence of donor-derived epithelial cells and hepatocytes.
Methods
Characteristics of the Donors and Recipients
Eleven patients received high-dose chemotherapy alone or chemotherapycombined with radiotherapy, followed by a transplant of allogeneicperipheral-blood stem cells (in 10 patients) or autologous peripheral-bloodstem cells (in 1 patient) for the treatment of hematologic cancersor breast cancer. One patient underwent allogeneic bone marrowtransplantation. Both myeloablative and nonmyeloablative10 regimenswere used before transplantation. All allogeneic grafts werederived from HLA-matched siblings. The peripheral-blood stemcells were obtained by apheresis after the donor had been treatedfor four days with recombinant human granulocyte colony-stimulatingfactor at a dose of 12 µg per kilogram of body weightper day. The total number of CD34+ cells transplanted rangedfrom 3.9x106 per kilogram of the recipient's body weight to14.8x106 per kilogram.
Six women received stem cells from a brother; five patientsreceived sex-matched stem cells, and one woman received autologousstem cells. The latter six patients served as controls. Hematopoieticstem-cell engraftment was verified by cytogenetic analysis orrestriction-fragment–length polymorphism (RFLP) analysis.11In three control patients, engraftment was documented on thebasis of the recovery of peripheral-blood cells alone.
Tissue Specimens
After stem-cell transplantation, tissue specimens were obtainedby a needle or punch biopsy that was performed for diagnosticpurposes. All 12 patients gave informed consent for biopsiesto be performed for diagnostic purposes. By the time our studybegan, all patients had died. The retrospective analysis ofbiopsy specimens was approved by the internal review board ofthe M.D. Anderson Cancer Center. All biopsies were performedfor the purpose of establishing the diagnosis of graft-versus-hostdisease.
A total of five consecutive sections were obtained from eachbiopsy specimen. Each section was 4 µm thick, which isapproximately half the thickness of a nucleus, with neighboringsections cut 4 µm apart. The sections closest to the centersection that was used for fluorescence in situ hybridizationwere those stained for cytokeratin and CD45 (leukocyte commonantigen), followed by those stained with hematoxylin and eosinand with a hepatocyte-specific antigen. This procedure allowedmatching fields to be as close to each other as possible.
Immunohistochemistry
Pretreatment of Slides
After removal of paraffin with xylene, tissue sections wererehydrated with graded alcohols (100 percent, 90 percent, and70 percent ethanol in distilled water) and washed with waterand phosphate-buffered saline. Endogenous peroxidase activitywas blocked by the application of 0.3 percent hydrogen peroxidein methanol for 15 minutes at room temperature, and the slideswere washed in phosphate-buffered saline again. Tissues werethen digested with 0.2 percent ficin (Sigma, St. Louis) in distilledwater for 15 minutes at room temperature and washed in phosphate-bufferedsaline.
Staining for Cytokeratin
For staining for cytokeratin, antigen retrieval was performedby incubating the tissue for eight minutes in 0.01 M citratebuffer in a microwave oven. Blocking serum (bovine serum albumin)was applied to the slides for 30 minutes at room temperature,and the slides were then incubated for 60 minutes at room temperaturewith monoclonal mouse antihuman cytokeratin antibodies (CAM5.2 [25 µg per milliliter; Becton Dickinson, San Jose,Calif.] at a dilution of 1:5 plus AE1/AE3 [1 mg per milliliter;Boehringer Mannheim, Indianapolis] at a dilution of 1:480).
Staining for CD45
For staining for CD45, antigen retrieval was performed by incubatingthe tissue for 45 minutes in TRIS-EDTA buffer in a steamer.Blocking serum (bovine serum albumin) was applied to the slidesfor 30 minutes at room temperature, and the slides were thenincubated with monoclonal mouse antibodies against CD45 (clonesPD7/26 and 2B11, Dako, Carpinteria, Calif.) at a dilution of1:300 for 45 minutes. To detect the antigen–antibody reaction,a streptavidin–biotin detection system (Super SensitiveImmunodetection System, Biogenex, San Ramon, Calif.) was usedaccording to the manufacturer's instructions. Sections fromtonsils and peripheral-blood smears were used as positive controls.
Staining for Hepatocytes
For staining for hepatocytes, antigen retrieval was performedby incubating the tissue for 45 minutes in TRIS-EDTA bufferin the steamer. Blocking serum (bovine serum albumin) was appliedto the slides for 30 minutes at room temperature, and then slideswere incubated with a monoclonal mouse IgG antihuman hepatocyteantibody (clone OCH1E5, Dako) at a dilution of 1:50 for 60 minutes.To detect the antigen–antibody reaction, we used a streptavidin–biotindetection system (Super Sensitive Immunodetection System, Biogenex)according to the manufacturer's instructions.
Fluorescence in Situ Hybridization
Paraffin-embedded slides were deparaffinized by baking in anoven overnight at 56°C and then clearing in xylene threetimes, for 10 minutes each, for a total of 30 minutes; theywere then dehydrated and air-dried. Slides were pretreated in0.2 N hydrochloric acid for 20 minutes, washed with water, andrinsed in 2x saline sodium citrate (SSC) (1x SSC is 0.15 M sodiumchloride and 0.015 M sodium citrate) for 3 minutes at room temperature.Slides were then incubated in 1 M sodium thiocyanate in distilledwater at 80°C for 30 minutes, washed with water, washedwith 2x SSC for 3 minutes, and air-dried. Tissue was digestedwith 1.5 µg of proteinase K (Sigma) per milliliter in0.2 N hydrochloric acid, pH 2.0, at 37°C for 1 hour, washedwith water, and then rinsed in 2x SSC for 3 minutes, air-dried,and fixed in Carnoy's solution (methanol and acetic acid ina 3:1 ratio) for 10 minutes. Slides were then denatured with70 percent formamide in 2x SSC at 73°C for five minutesand rinsed with 70 percent ethanol for three minutes, dehydrated,and air-dried. The mixture of probes for the X and Y chromosomes(Vysis, Downers Grove, Ill.) was denatured at 74°C for fiveminutes and applied to the denatured tissue. The slides werecovered with a coverslip, sealed with rubber cement, and incubatedin a humid chamber overnight at 37°C for hybridization.After 16 hours of hybridization, slides were washed in 0.4xSSC containing 0.3 percent Nonidet P-40 for two minutes at 73°C,transferred to 2x SSC containing 0.1 percent Nonidet P-40 forone minute at room temperature, and drained. Slides were thencounterstained with 10 µl of 4',6-diamidine-2-phenylidoledihydrochloride (DAPI, Boehringer Mannheim) at a concentrationof 14 µg per milliliter of VectaShield mounting medium(Vector Laboratories, Burlingame, Calif.), and a coverslip wasapplied.
Quantification of XY-Positive, Donor-Derived Nonlymphohematopoietic Cells
The slides were scanned at a magnification of 100 under a fluorescencemicroscope (Leica, Wetzlar, Germany) equipped with an epi-illuminationsystem, a 100-W mercury lamp, and a set of filters, includingDAPI single-bandpass (DAPI counterstain), Spectrum Orange single-bandpass,Spectrum Green single-bandpass, and Red/Green dual-bandpassfilters (all from Vysis). A total of 200 nonoverlapping cellsand nuclei with distinct cells were counted, and the Y-positive(red) and X-positive (green) signals were identified. The percentageof cells that were XY-positive or XX-positive was less than100 percent because of the truncation of nuclei during sectioningand incomplete hybridization. The stringent criteria used incounting positive signals led to an underestimation of the percentagesof XX- or XY-positive cells in cases of female-to-female ormale-to-male transplantation. Fields were matched to the correspondingfields in photomicrographs of the variously stained slides accordingto the location and architecture of the tissue on the slide.Matching microscopic fields were either 4 µm apart (inthe slides stained with antibodies against cytokeratin or CD45)or 8 µm apart (in the slides stained with hematoxylinand eosin or the anti-hepatocyte antibody). The slides stainedwith hematoxylin and eosin and with antibody against CD45 werecarefully evaluated to exclude the presence of lymphocytes,monocytes, and granulocytes, and XY-positive epithelial cellswere identified with the use of only those cells that couldreliably be classified on the basis of their staining properties.
Staining for Cytokeratin and Fluorescence in Situ Hybridization
Slides were prepared for staining for cytokeratin as describedabove. They were then washed in 1x phosphate-buffered salinefor 5 minutes, and Texas Red–conjugated donkey antimouseIgG (Jackson ImmunoResearch Laboratories, West Grove, Pa.) ata dilution of 1:200 was applied for 60 minutes. After they hadbeen washed in phosphate-buffered saline for five minutes, theslides were counterstained with 10 µl of DAPI at a concentrationof 14 µg per milliliter of VectaShield antifade solution(Vector Laboratories). After they were stained for cytokeratin,the sections were systematically scanned and photographed ata magnification of 63 with the use of a calibrated and automatedmotorized stage. Next, the slides were washed in phosphate-bufferedsaline for five minutes and prepared for fluorescence in situhybridization as outlined above. The slides were then scannedfor XY-positive cells; pictures were taken at a magnificationof 63 and were matched with the stored cytokeratin images.
Results
Characteristics of Patients and Transplantations
The characteristics of the donors and recipients, the type ofregimen used before transplantation, and the quantity of CD34+cells transfused are presented in Table 1.
Table 1. Characteristics of the Donors and the Recipients.
Hematopoietic Chimerism after Allogeneic Stem-Cell Transplantation
Complete hematopoietic chimerism was demonstrated by RFLP analysisin four of the six recipients of sex-mismatched stem cells (Patients7, 8, 10, and 12) and by cytogenetic analysis of bone marrowcells in all six (Table 2). In three of the six control patients,donor chimerism was documented by RFLP analysis.
Table 2. Incidence of Donor Chimerism and Biopsy Reports.
Donor-Derived Epithelial Cells and Hepatocytes in Recipients of Sex-Mismatched Stem Cells
We studied biopsy specimens of skin, liver, and gastrointestinaltract for the presence of donor-derived epithelial cells andhepatocytes. Whereas a DNA probe specific for the centromeresdetected X and Y chromosomes in 35 to 75 percent of cells inbiopsy specimens from the three male patients who received anallograft from a male donor (Patients 4, 5, and 6) (Table 3),they did not detect XY-positive cells in any biopsy specimensfrom women who received a stem-cell transplant from a sister(Patients 1 and 2) or the woman who received her own cells (Patient3). By contrast, XY-positive cells were present in biopsy specimensof the skin, liver, or gastrointestinal tract from the fivefemale recipients of peripheral-blood stem cells from male donors(Patients 7, 8, 10, 11, and 12) and in the female recipientof a bone marrow allograft from her brother (Patient 9).
Table 3. Percentage of XY-Positive Cells in Various Tissue Biopsy Specimens from Six Control Recipients of Sex-Matched Stem-Cell Allografts or Autograft and Six Recipients of Sex-Mismatched Stem-Cell Allografts.
In epidermal tissue of the skin, donor-derived cells were locatedin the deep layer of Malpighi (the stratum spinosum of the stratumgerminativum), close to the dermal–epidermal junctionand the stratum granulosum (Figure 1). In the liver, XY-positivehepatocytes were distinguished by large, round nuclei and abundantgranular cytoplasm (Figure 2). In the glandular epithelium ofthe gastric cardia, cells containing the Y chromosome were foundin the foveolae or tubular pits of the superficial glandularlayer, which is composed of mucus-containing cells lining thefoveolae (Figure 3). The organ specificity of these cells wasindicated by their location, staining for cytokeratins and hepatocytes(in the liver), and the absence of CD45.
Figure 1. Donor-Derived Epidermal Cells in the Skin of a Female Recipient (Patient 10) of Peripheral-Blood Stem Cells from a Male Donor.
Neighboring tissue sections were stained with hematoxylin and eosin (Panel A), CD45 (Panel B), and cytokeratin (Panel C) and were examined by interphase fluorescence in situ hybridization for centromeres of X (green) and Y (red) chromosomes (Panel D). Panels E and F show a single tissue section that was first stained with fluorescent cytokeratin (Panel E) and then examined by fluorescence in situ hybridization (Panel F). The cells are predominantly epithelial in nature (cytokeratin-positive and CD45-negative) and of female origin (XX-positive). A smaller population of XY-positive epithelial cells (inset and arrow in Panel D) is also present. Cells shown in Panels E and F are both cytokeratin-positive and XY-positive (arrows). (Panels A through F, x63; inset in Panel D, x160.)
Figure 2. Donor-Derived Hepatocytes in the Liver of a Female Recipient (Patient 7) of Peripheral-Blood Stem Cells from a Male Donor.
Neighboring tissue sections were stained with hematoxylin and eosin (Panel A), CD45 (Panel B), and cytokeratin (Panel C) and were examined by interphase fluorescence in situ hybridization for centromeres of X (green) and Y (red) chromosomes. Panels E and F show a single tissue section that was first stained with fluorescent cytokeratin (Panel E) and then examined by fluorescence in situ hybridization (Panel F). Most cells are cytokeratin-positive, CD45-negative, and XX-positive. A small population of XY-positive cells (inset and arrows in Panel D) is also present. Cells shown in Panels E and F are both cytokeratin-positive and XY-positive (arrows). (Panels A through F, x63; inset in Panel D, x160.)
Figure 3. Donor-Derived Mucosal Cells in the Gastric Cardia in a Female Recipient (Patient 7) of Peripheral-Blood Stem Cells from a Male Donor.
Neighboring tissue sections were stained with hematoxylin and eosin (Panel A), CD45 (Panel B), and cytokeratin (Panel C) and were examined by interphase fluorescence in situ hybridization for centromeres of X (green) and Y (red) chromosomes. Panels E and F show a single tissue section that was first stained with fluorescent cytokeratin (Panel E) and then examined by fluorescence in situ hybridization (Panel F). Most cells are cytokeratin-positive, CD45-negative, and XX-positive. Some XY-positive cells (inset and arrows in Panel D) are also present. Cells shown in Panels E and F are both cytokeratin-positive and XY-positive (arrows). (Panels A through F, x63; inset in Panel D, x160.)
We also analyzed slides from biopsy specimens of all three organsafter they had been stained with anti-cytokeratin antibodiesand examined by fluorescence in situ hybridization with probesfor the X and Y chromosomes. XY-positive signals in cytokeratin-positivecells would indicate the epithelial character of donor-derivedcells. As demonstrated in epidermal cells in skin (Figure 1Eand Figure 1F), hepatocytes (Figure 2E and Figure 2F) and mucosalcells of the gastrointestinal tract (Figure 3E and Figure 3F),XY-positive signals were detectable in cytokeratin-positivecells.
The frequency of XY-positive cells in biopsy specimens fromfemale recipients of grafts from male donors ranged from 0 to7 percent (Table 3). XY-positive cells were detected in livertissue as early as 13 days after transplantation (in Patient8) and were seen in skin tissue 354 days after transplantationof peripheral-blood stem cells (in Patient 10) and 867 daysafter transplantation of bone marrow (in Patient 9). The biopsyreports and the patients' clinical status at the time of biopsydid not suggest that donor-cell engraftment was more likelyin tissues injured by graft-versus-host disease than in othertissues (as shown by the results for Patients 7, 10, 11, and12 in Table 2).
Discussion
Circulating blood is known to contain stem cells that can completelyrestore hematopoiesis after ablation of the bone marrow.12,13Recently, mesenchymal stem cells with a capacity for self-renewaland the potential to differentiate into bone, cartilage, fat,tendon, muscle, or marrow stroma have been identified in humanbone marrow.1,14 Whether such stem cells circulate in the bloodis unsettled.15,16,17 A stem cell in rat bone marrow has beenfound to differentiate into the epithelial lineage that generateshepatic oval cells,2 and in mice with a metabolic defect thatimpairs liver function, the infusion of purified hematopoieticstem cells can restore both hematopoiesis and liver function.18Progenitors in mouse bone marrow have also been shown to bemyogenic and can induce muscle regeneration.5,6
The existence of stem cells with multiple differentiating capabilities19was conclusively demonstrated by Krause et al.,20 who showedthat a single bone marrow stem cell not only can restore hematopoiesisin mice that have received otherwise lethal doses of radiationbut also can differentiate into mature epithelial cells of theskin, lungs, and gastrointestinal tract. Moreover, human progenitorcells transplanted into fetal sheep have been reported to differentiateinto hematopoietic cells and hepatocytes.21 There is also evidencethat human kidney,22 liver, and muscle cells23 can transforminto blood-forming cells. Moreover, two groups have reportedthe presence of donor-derived hepatocytes and cholangiocytesin recipients of sex-mismatched bone marrow transplants.3,4
Our findings indicate that human blood contains stem cells thatcan differentiate into cells of the liver, gastrointestinaltract, and skin. The origin of these stem cells and the wayin which they generate hepatocytes and epithelial cells areunknown. It is possible that multiple lineage-restricted stemcells in the circulating blood can differentiate independentlyinto their corresponding mature tissue. Alternatively, primitiveadult multipotent stem cells may give rise to differentiated,lineage-restricted stem cells that can generate mature cells.It is also possible that stem cells that are committed to differentiationprimarily along a particular pathway (e.g., hematopoiesis) canswitch to another lineage under the influence of signals ofthe local microenvironment. Beltrami and coworkers24 have postulatedthat circulating stem cells differentiate into dividing myocytesthat repair necrotic myocardium after infarction in humans.It is also conceivable that, in addition to mobilizing hematopoieticstem cells, recombinant human granulocyte colony-stimulatingfactor mobilizes clonogenic cells of epithelial origin intothe peripheral blood.25
Technically, our studies of thin tissue sections are not infallible.Nonhematopoietic tissue may harbor a few lymphohematopoieticcells that standard histologic staining techniques fail to detect.In our study, we used a restricted number of consecutive tissuesections and used stringent criteria in the enumeration of XY-positivecells. Furthermore, to ensure that the X- and Y-chromosome signalson fluorescence in situ hybridization were indeed detected incytokeratin-positive cells, we used sequential staining of thesame tissue sections. This procedure, however, exposed the tissueto rough conditions, which may have led us to underestimatethe numbers of donor-derived cells in tissue sections.
Tissue damage caused by radiation, chemotherapy, or graft-versus-hostdisease, among other causes, is believed to be responsible forthe homing of peripheral-blood stem cells and their differentiationinto various solid-organ–specific tissues.19 Our resultsindicate a rather uniform pattern of engraftment of donor-derivedhepatocytes and epithelial cells irrespective of the presenceor absence of tissue damage caused by graft-versus-host disease.In conclusion, our findings suggest the existence of a populationof circulating stem cells with the capacity to differentiateinto epithelial cells and hepatocytes. The physiologic roleof these cells is currently unknown.
We are indebted to Drs. S. Giralt, I. Khouri, K. vanBesien,R. Mehra, D. Przepiorka, J. Gajewski, and D. Claxton of theUniversity of Texas M.D. Anderson Cancer Center Bone MarrowTransplant Service for their clinical contributions; to Drs.H. Zang and F. Jiang for their technical expertise; and to Ms.K. Suilleabhain for editing the manuscript.
Source Information
From the Departments of Blood and Marrow Transplantation (M.K., G.R., R.E.C.), Pathology (R.L.K., A.K., A.C.R.), Hematopathology (M.A.), and Bioimmunotherapy (Z.E.), University of Texas M.D. Anderson Cancer Center, Houston.
Address reprint requests to Dr. Körbling at the University of Texas M.D. Anderson Cancer Center, Department of Blood and Marrow Transplantation, Box 423, 1515 Holcombe Blvd., Houston, TX 77030, or at mkorblin{at}mdanderson.org.
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