Federico Quaini, M.D., Konrad Urbanek, M.D., Antonio P. Beltrami, M.D., Nicoletta Finato, M.D., Carlo A. Beltrami, M.D., Bernardo Nadal-Ginard, M.D., Ph.D., Jan Kajstura, Ph.D., Annarosa Leri, M.D., and Piero Anversa, M.D.
Background Cases in which a male patient receives a heart froma female donor provide an unusual opportunity to test whetherprimitive cells translocate from the recipient to the graftand whether cells with the phenotypic characteristics of thoseof the recipient ultimately reside in the donor heart. The Ychromosome can be used to detect migrated undifferentiated cellsexpressing stem-cell antigens and to discriminate between primitivecells derived from the recipient and those derived from thedonor.
Methods We examined samples from the atria of the recipientand the atria and ventricles of the graft by fluorescence insitu hybridization to determine whether Y chromosomes were presentin eight hearts from female donors implanted into male patients.Primitive cells bearing Y chromosomes that expressed c-kit,MDR1, and Sca-1 were also investigated.
Results Myocytes, coronary arterioles, and capillaries thathad a Y chromosome made up 7 to 10 percent of those in the donorhearts and were highly proliferative. As compared with the ventriclesof control hearts, the ventricles of the transplanted heartshad markedly increased numbers of cells that were positive forc-kit, MDR1, or Sca-1. The number of primitive cells was higherin the atria of the hosts and the atria of the donor heartsthan in the ventricles of the donor hearts, and 12 to 16 percentof these cells contained a Y chromosome. Undifferentiated cellswere negative for markers of bone marrow origin. Progenitorcells expressing MEF2, GATA-4, and nestin (which identify thecells as myocytes) and Flk1 (which identifies the cells as endothelialcells) were identified.
Conclusions Our results show a high level of cardiac chimerismcaused by the migration of primitive cells from the recipientto the grafted heart. Putative stem cells and progenitor cellswere identified in control myocardium and in increased numbersin transplanted hearts.
The interaction between donor and recipient cells after transplantationhas received great attention in an attempt to identify the basisof rejection and graft-versus-host disease.1,2,3 Cell migrationfrom the allograft to the recipient results in systemic chimerism,1,4and cell migration from the host to the transplanted organ resultsin chimerism in the organ.2,5 Chimerism may be detected easilyafter sex-mismatched organ transplantation with the use of fluorescencein situ hybridization for the Y chromosome.6,7,8 Systemic chimerismmay be recognized when a female host receives an organ froma male donor, and chimerism may be identified in the organ afterthe transplantation of an organ from a female donor into a malepatient. The origin and fate of recipient cells in the transplantedhuman heart are unknown. At present, there is no proof thatchimerism leads to the generation of differentiated myocytesand intact coronary-artery branches.9,10 Experimental evidencepoints to the contribution of the host's cells to neointimalthickening of intramural coronary vessels and transplant-relatedvasculopathy.11,12 However, the formation of normal myocytes,arterioles, and capillaries has not been shown to occur in thegrafted heart. Recent demonstrations of the ability of primitivecells to mobilize and home to the infarcted heart13,14,15 haveraised the possibility that undifferentiated cells may translocatefrom the recipient to the graft, contributing to ventricularremodeling. These cells, together with circulating endothelial-and smooth-muscle–cell progenitors,16,17 could colonizethe new heart. Such a form of chimerism could regenerate myocardiumand sustain cardiac performance.
To test this hypothesis, we studied male patients who receivedhearts from female donors. Normal hearts obtained at autopsyfrom male and female cadavers were used to establish the efficiencyand specificity, respectively, of fluorescence in situ hybridization.Three surface markers were used for the identification of primitivecells: c-kit, which is the receptor for stem-cell factor18;MDR1, which is a P-glycoprotein capable of extruding dyes, toxicsubstances, and drugs19; and Sca-1, which is involved in cellsignaling and cell adhesion.20
Methods
Hearts and Detection of the Y Chromosome
Eight hearts from female donors transplanted into male recipientswere investigated. Permission for postmortem examination wasobtained from the next of kin. Portions of the recipients' atriathat had been retained and sutured to the atria of the transplantedheart at the time of surgery and the atria and left ventricleof the donor hearts were sampled, fixed in formalin, and embeddedin paraffin.21 Normal hearts obtained at autopsy from six maleand four female cadavers were used as controls. Four sectionsfrom each atrium of the recipient, four sections from each atriumof the donor heart, and six sections from the left ventricleof the donor heart were analyzed in each case.
The Y chromosome was detected by fluorescence in situ hybridizationin nuclei in interphase with the use of the DNA probe CEP Ysatellite III (Vysis, Downers Grove, Ill.).7 Nuclei were stainedwith propidium iodide14; 16,834 nuclei were counted in myocytes,25,642 in coronary arterioles, and 15,539 in capillaries.
Cell Markers
Antibodies against c-kit (Dako, Carpinteria, Calif.), MDR1 (Chemicon,Temecula, Calif.), and Sca-1 (Cedarlane, Hornby, Ont., Canada)were used to identify primitive cells.14 Myocytes were recognizedby means of antibodies against sarcomeric -actin (Sigma, St.Louis), cardiac myosin heavy chain (Chemicon), desmin (Sigma),connexin 43 (Sigma), GATA-4 (Santa Cruz, Santa Cruz, Calif.),MEF2D (Santa Cruz), and nestin (Developmental Studies HybridomaBank, Iowa City, Iowa). Smooth-muscle cells were identifiedby means of antibodies against smooth-muscle -actin (Sigma);fibroblasts were identified by means of antibodies against vimentin(Sigma) in the absence of factor VIII. Antibodies against Flk1(Santa Cruz), factor VIII (Sigma), and CD31 (Santa Cruz) wereused to detect endothelial cells. Antibodies against CD45, CD45ROand CD8 (Dako), and glycophorin A (Sigma) were used to detectmyeloid, lymphoid, and erythroid cells, respectively. IgG antibodiesconjugated with fluorescein isothiocyanate, cytochrome CY5,or tetramethylrhodamine isothiocyanate were used as secondaryantibodies.14,21 Ki-67 in nuclei was evaluated with the useof anti–Ki-67 antibodies (Diagnostic Biosystems, Pleasanton,Calif.).21
Statistical Analysis
Results are presented as means ±SD. The significanceof differences between two measurements was determined by Student'st-test; for multiple comparisons the Bonferroni method was used.22
Results
Study Patients
Data on age, primary disease, and the time from the onset ofheart failure to transplantation are shown in Table 1, alongwith the time from transplantation to death and the weight ofthe implanted heart at the time of death. The female donorswere a mean (±SD) of 43±15 years old and had diedof cerebral hemorrhage or trauma. The donor hearts remainedimplanted for a period ranging from 4 to 552 days. The transplantrecipients were treated with conventional immunosuppressivetherapy. With one exception, only low levels of rejection (gradeI) were detected. The average weight of the recipients' heartswas greater than that of the donor hearts, because hearts weretransplanted from female donors into diseased male patients.The smaller size of the transplanted heart and terminal cardiacfailure in the recipients imposed a dramatic increase in workloadon the implanted heart.
Table 1. Clinical and Anatomical Characteristics of the Patients.
Y Chromosome
The left ventricular sections from six normal control heartsfrom male cadavers showed Y chromosomes in a mean (±SD)of 44±4 percent of myocytes (nuclei sampled, 6000; Y-chromosome–positivenuclei, 2647), 50±6 percent of coronary arterioles (arteriolessampled, 587; Y-chromosome–positive arterioles, 293),and 46±7 percent of capillaries (nuclei sampled, 2440;Y-chromosome–positive nuclei, 1122). The prevalence ofY chromosomes in the nuclei of the vascular smooth-muscle cellsof individual arterioles varied both within and among heartsand ranged from 31 percent (5 of 16 nuclei) to 75 percent (12of 16 nuclei). The hybridization signal consisted of a singledot at the periphery of the nucleus. Four normal hearts fromfemale cadavers were used as negative controls, and in 32 sections(8 from each heart), no myocyte nucleus, smooth-muscle–cellnucleus, or endothelial-cell nucleus contained the Y chromosome.On the basis of the data collected from the examination of thehearts from male cadavers that were used as controls for evaluatingthe assay, our method underestimated the frequency of positivecells by nearly 50 percent. However, it was highly specific.
The pattern of Y-chromosome labeling in the myocytes and coronaryvessels of the hearts transplanted from female cadavers (Figure 1A to 1H)was identical to that found in the control heartsfrom male cadavers. Chimerism was present in all of the transplantedhearts. The quantitative evaluation was restricted to myocytesand coronary vessels with normal structure. Areas with myointimalthickening or tissue damage were excluded from the measurementsin order to avoid sites of injury in which circulating inflammatoryand immunoreactive cells could have lodged. Blood-cell migrationoccurs in animals2,4,5 and humans after the transplantationof a heart, a kidney, or a liver.1 Our objective was to elucidatethe role of chimerism in the undamaged myocardium.
Figure 1. The Y Chromosome in Transplanted Hearts.
The arrowheads indicate the Y chromosomes in myocytes (Panels A and B), smooth-muscle cells (Panels C and D), and endothelial cells in both coronary arterioles (Panels E and F), and capillary endothelial cells (Panels G and H), and in the nuclei of a myocyte (Panel I), a smooth-muscle cell (Panel J), and a capillary endothelial cell (Panel K). In Panels A through H, the blue areas show the propidium iodide staining in nuclei, and the green areas indicate the Y chromosomes in nuclei. The red areas indicate the presence of sarcomeric -actin in Panel B, of smooth-muscle -actin in Panel D, and of factor VIII in Panels F and H. In Panels I, J, and K, the bright blue, fluorescent areas and the arrows indicate the presence of Ki-67, and the yellow areas show the Y chromosomes. The scale bars represent 10 µm.
In the transplanted hearts, similar percentages of myocytes(9±4 percent), arterioles (10±3 percent), andcapillaries (7±1 percent) contained the male chromosome.Arterioles were considered positive when a minimum of 30 percentof smooth-muscle cells had the Y chromosome. Often, more than45 percent of these cells carried the Y chromosome. The fractionof male endothelial cells in the lumen of arterioles variedfrom 21 to 50 percent. The absence of CD45 on the surface ofthese cells indicated that they were not inflammatory infiltrates.The 50 percent efficiency of fluorescence in situ hybridizationfor the Y chromosome implied that at least 60 percent of smooth-musclecells and 42 percent of endothelial cells in the arteriolarwall were of male origin. The high level of chimerism in arterioleswas consistent with the formation of resistance vessels in therecipient. Cells from the host were responsible for the developmentof 14 percent of the capillaries (Figure 1H). Because of thesmall number of patients, we could not study the correlationbetween the time from transplantation to death and the levelof chimerism present in myocytes, arterioles, and capillaries.However, the highest levels of chimerism in myocytes (15 percent),arterioles (12 percent), and capillaries (9 percent) were foundbetween 4 and 28 days after transplantation. Conversely, thelowest levels of chimerism in myocytes (4 percent), arterioles(7 percent), and capillaries (5 percent) were noted between396 and 552 days after transplantation. Most Y-chromosome–bearingcells were fully mature and indistinguishable from adjacentand distant negative cells. Occasionally, small myocytes wereobserved.
Cell proliferation was measured with the use of Ki-67 labelingcombined with Y-chromosome labeling (Figure 1I, 1J, and 1K).Nine percent of myocytes contained the Y chromosome, and a meanof 17.2±4.2 percent of this group of cells were replicating(nuclei counted, 862). In contrast, only 1.0±0.3 percentof the remaining 91 percent of myocytes were replicating. Similarly,13.6±4.8 percent of the 10 percent of smooth-muscle cellsthat were male (nuclei counted, 1165) and 16.0±4.9 percentof the 7 percent of endothelial cells that were male (nucleicounted, 1141) were replicating. Of the remaining 90 percentof smooth-muscle cells and 93 percent of endothelial cells,0.8±0.2 percent and 1.1±0.3 percent, respectively,were replicating. Y-chromosome–positive mitotic myocytes,endothelial cells, and smooth-muscle cells were found.
Primitive Cells and the Transplanted Heart
Another objective of this study concerned the origin of malecells that translocated and differentiated in hearts transplantedfrom female donors. In six cases, during cardiac transplantation,portions of both atria of the recipient were sutured to thepartially dissected atria of the donor. In the other two cases,only the left atrium of the recipient was maintained, since,on the right side, an anastomosis was performed between thevena cava of the recipient and that of the donor heart. Thepresence of hybrid atria raised the question of whether undifferentiatedcells migrated from the host to the graft through the systemiccirculation or homed to the ventricles from the native atrialtissue that had been preserved. Circulating primitive cellswere not evaluated. However, primitive cells in the atria ofthe recipient and the atria and left ventricle of the donorwere measured after they had been identified by means of c-kit,MDR1, and Sca-1. These surface proteins are present in stemcells but are not exclusive to this type of cell.18,23,24,25,26
Cells expressing c-kit, MDR1, or Sca-1 (Figure 2A, 2B, and 2C)were identified in the atria and left ventricle. These weresmall, round cells with a large nucleus and a thin rim of cytoplasm.The colocalization of c-kit and MDR1 in these cells was alsodocumented (Figure 2D, 2E, and 2F). Sca-1 was not found in cellsthat contained c-kit or MDR1. The undifferentiated cells werenegative for markers of bone marrow–derived cells, suchas leukocyte common antigen (CD45), lymphoid lineage (CD45ROand CD8), and erythroid progeny (glycophorin A) (Figure 2J, 2K, 2L, 2M, and 2N).These cardiac cells were negative for markersof differentiated myocytes (cardiac myosin heavy chain, sarcomeric-actin, desmin, and connexin 43), endothelial cells (CD31, factorVIII, and vimentin), smooth-muscle cells (smooth-muscle -actinand desmin), and fibroblasts (vimentin). In addition, fluorescencein situ hybridization assays for the Y chromosome were evaluatedin these primitive cells in samples from the atria and leftventricle of the donor (Figure 2G, 2H, and 2I).
Figure 2. Primitive Cells Expressing MDR1, c-kit, and Sca-1 in Transplanted Hearts and the Native Atria of Recipients.
Panels A, B, and C show the native atrium of a transplant recipent; the arrowheads indicate the presence of MDR1 in primitive cells; R-A denotes the direction of the recipient atrium, and D-A the direction of the donor atrium. Panels D, E, and F show c-kit and MDR1 in a primitive cell in the atrium of a donor heart. The blue areas in Panels A through F show the propidium iodide staining in nuclei; the green areas in Panels B, C, E, and F indicate the presence of MDR1; the yellow areas in Panels D and F indicate the presence of c-kit; and the red areas in Panels C and F indicate the presence of sarcomeric -actin. Panels G, H, and I show Y chromosomes (light green, arrowheads) in an atrial cell expressing c-kit (Panel G, red, arrow), a ventricular cell expressing MDR1 (Panel H, red, arrow), and a ventricular cell expressing Sca-1 (Panel I, red, arrow); the green areas indicate the presence of sarcomeric -actin. In Panel J, a cell expressing c-kit (green, arrow) is negative for CD45 (red, arrowheads); in Panel K, a cell expressing MDR1 (green, arrow) is negative for CD45 (red, arrowheads); in Panel L, a cell expressing c-kit (green, arrow) is negative for glycophorin A (red, arrowheads); in Panel M, a cell expressing MDR1 (green, arrow) is negative for CD45RO (red, arrowheads); and in Panel N, a cell expressing Sca-1 (green, arrow) is negative for CD8 (red, arrowheads). The scale bars represent 10 µm.
The 10 left ventricles from the control hearts had low numbersof cells that were positive for c-kit, MDR1, or Sca-1 (Figure 3).In the left ventricles of the eight hearts transplantedfrom female donors, the number of cells expressing c-kit was4.0 times as high as that in the control hearts (P<0.001);the number of cells expressing MDR1 was 3.9 times as high (P<0.001);and the number of cells expressing Sca-1 was 6.0 times as high(P<0.001). Values for the residual atrial portion of therecipients were similar to those for the atria of the donorhearts but were much higher than those for the left ventricleof the donor hearts (Figure 3). The prevalence of primitivecells expressing c-kit was 1.3 times as high in the atria ofthe donor hearts as in the ventricle of the donor hearts (P=0.006);the prevalence of primitive cells expressing MDR1 was 2.4 timesas high (P<0.001); and the prevalence of primitive cellsexpressing Sca-1 was 2.6 times as high (P<0.001) (Figure 3).In the atria and ventricles of the donor hearts, 12 to 16percent of the cells positive for c-kit, MDR1, or Sca-1 containedthe Y chromosome. In donor and recipient myocardium, 29 to 40percent of the c-kit–positive cells also expressed MDR1.Similarly, 14 to 18 percent of MDR1-positive cells also expressedc-kit.
Figure 3. Numbers of Primitive Cells Expressing c-kit, MDR1, and Sca-1 in the Left Ventricle of Transplanted Hearts and Control Hearts and in the Atria of Transplanted Hearts and Transplant Recipients.
The numbers of cells expressing c-kit, MDR1, and Sca-1 counted in the native atria of recipients were 633, 971, and 481, respectively. Values for the atria of the donor hearts were 647, 1233, and 556, respectively; values for the left ventricle of the donor hearts were 163, 405, and 178, respectively; and values for the left ventricle of the control hearts were 48, 55, and 24, respectively. P<0.05 for all comparisons with the control hearts and for all comparisons with the left ventricle of the donor hearts.
Chimerism and Amplifying Cardiac Cells
To identify the cells involved in the generation of myocytesand vessels of host origin in the heart transplanted from afemale donor, early markers of cardiac-cell lineages were identified.The transcription factors MEF2D and GATA-4 were recognized inY-chromosome–bearing cells (Figure 4A and Figure 4B),documenting that these cells were committed to myocyte differentiation.Moreover, Flk1 receptor was detected (Figure 4C), suggestingthe involvement of endothelial and smooth-muscle cell lineages.The intermediate filament protein nestin was also observed (Figure 4D),implying a more advanced stage of myocyte differentiation.27Although Figure 4 provides examples of the presence of theseproteins in Y-chromosome–positive cells, the majorityof cardiac cells with these markers had negative results onfluorescence in situ hybridization. These indicators of celldifferentiation were not seen in primitive cells that expressedonly c-kit, MDR1, or Sca-1.
Figure 4. MEF2D (Panel A), GATA-4 (Panel B), Flk1 (Panel C), and Nestin (Panel D) in Committed Cells (Red, Arrows) Containing the Y Chromosome (Yellow, Arrowheads).
The blue areas show propidium iodide staining in the nuclei; the green areas indicate the presence of sarcomeric -actin. The scale bars represent 10 µm.
Discussion
We report here that undifferentiated cells were found in controlhuman hearts and that their number increased significantly inhearts from female donors that were transplanted into male recipients.These primitive cells expressed on their surface stem-cell–relatedantigens including c-kit, MDR1, and Sca-1.18,19,20 A fractionof these cells were Y-chromosome–positive, providing directevidence of their origin: they had translocated from the hostto the atria and ventricles of the grafted heart. Loss of stem-cellmarkers, active proliferation, and acquisition of the maturephenotype followed the cell colonization. New myocytes, coronaryarterioles, and capillaries were formed.
After large infarcts, lineage-negative, c-kit–positive,14CD34-positive13 and highly enriched hematopoietic stem cells(side population) of the bone marrow15 migrate to damaged areasand promote repair. Although tissue injury occurs with transplantation,9,12,28we observed that myocytes and coronary vessels were generatedwithin the intact myocardium. Through growth and differentiation,male primitive cells contributed to the remodeling of the hearttransplanted from a female donor. This conclusion is consistentwith the determination that 18 percent of myocytes, 20 percentof coronary arterioles, and 14 percent of capillaries were ofmale origin, according to the values that result when the 50percent efficiency of the fluorescence in situ hybridizationassay is taken into account.
The source of primitive cells that lead to cardiac chimerismis difficult to identify. Circulating hematopoietic stem cellsfrom the recipient could have homed to the implanted heart.13,15Early indicators of bone marrow cell differentiation were notdetected in cells expressing c-kit, MDR1, or Sca-1, whetheror not they had the Y chromosome. However, these findings donot preclude the possibility that stem cells were mobilizedfrom the bone marrow and reached the implanted heart. In thegraft, a high number of undifferentiated cells were Y-chromosome–negative,suggesting that groups of primitive cells reside in the heartand, together with the cells translocated from the host, multiplyand acquire cardiac-cell lineages. At present, it is impossibleto establish whether replicating female cells originate fromstem cells or derive from subpopulations of nonterminally differentiatedcells.
Chimerism in transplanted organs has been linked to the processof rejection.1,2,28 It has been claimed that cell death, inflammatoryinfiltrates, and the release of cytokines characterize the immunoreactiveresponse.29,30,31 Humoral factors may act as molecular signalsfor the chemoattraction and activation of quiescent primitivecells. Cardiac chimerism was not previously identified in humans,because this phenomenon was considered to be restricted to hemolymphopoieticcells.1,2,28 Our results contrast with previous observations.9,10More refined techniques and the use of confocal microscopy withenhanced resolution14 have improved the analysis of the myocardium.
We can only speculate as to the pathobiologic sequence of events.When it is transplanted, the donor heart has to reverse theclinical manifestations of end-stage heart failure in the recipient,32,33including an increased hemodynamic load. These mechanical factorsmost likely stretch the myocardium while triggering the translocationof undifferentiated cells clustered in the host's native atriumand concurrently activate resident cells in the transplantedheart. Locally distributed primitive cells and those that havemigrated from the systemic circulation may contribute to optimizingcardiac mass and restoring function in the short term. Severedepression in ventricular performance with the progression ofcoronary vasculopathy and tissue damage28,29,30 may sustainover the long term the growth-promoting effects of native andcolonizing primitive cells in the transplanted heart.
The high degree of differentiation of the myocytes, coronaryarterioles, and capillaries that originated from male cellsand were present in the transplanted heart suggests that cellmigration occurred early and involved primitive cells (i.e.,stem cells) and precursor cells (i.e., committed progenitors).Precursor cells proliferate much more rapidly than primitivecells, undergo differentiation, and acquire functional competence.34Y-chromosome–positive cells from the graft whose hostsurvived only four days after transplantation were indistinguishablefrom those of transplants of longer duration and from the host'scells. Because the earliest migration date of these cells wasthe date of transplantation, their mature phenotype indicatesthat the migration of primitive cells into the transplantedheart, cell differentiation, and phenotypic maturation wererapid processes. This temporal sequence is more reminiscentof organ morphogenesis and cell differentiation during embryonicand fetal development than of the rate of organ remodeling expectedin an adult. The identification of male progenitor cells expressingMEF2D, GATA-4, nestin, and Flk1 supports this contention.
An important question concerns whether, at the completion ofdifferentiation, each cardiac-cell lineage reaches an arrestof growth so that the ability to replicate is permanently lost.Endothelial and smooth-muscle cells continue to grow in vitro35,36and in vivo.36,37 Mitotic division and cell regeneration ofmyocytes also occur in vivo in the adult heart in animals andhumans,21,38 but mature myocytes do not proliferate in vitro.39Thus, it seems that there are resident cardiac stem cells invivo that differentiate into myocytes in normal and diseasedhearts. These cells are not confined to restricted regions ofthe heart; they migrate where they are needed, as demonstratedby the high level of cardiac chimerism found in this study.
Supported by grants (HL-38132, HL-39902, AG-15756, HL-65577,HL-66923, HL-65573, and AG-17042) from the National Institutesof Health.
The monoclonal antibody Rat-401 (anti-nestin) developed by Hockfieldwas obtained from the Developmental Studies Hybridoma Bank atthe Department of Biological Sciences, University of Iowa, IowaCity, operating under the auspices of the National Instituteof Child Health and Human Development.
Source Information
From the Department of Medicine, New York Medical College, Valhalla (F.Q., K.U., A.P.B., B.N.-G., J.K., A.L., P.A.); and the Department of Pathology, University of Udine, Udine, Italy (N.F., C.A.B.).
Address reprint requests to Dr. Anversa at the Department of Medicine, Vosburgh Pavilion, New York Medical College, Valhalla, NY 10595, or at piero_anversa{at}nymc.edu.
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[Abstract][Full Text]
Fernandez-Aviles, F., San Roman, J. A., Garcia-Frade, J., Fernandez, M. E., Penarrubia, M. J., de la Fuente, L., Gomez-Bueno, M., Cantalapiedra, A., Fernandez, J., Gutierrez, O., Sanchez, P. L., Hernandez, C., Sanz, R., Garcia-Sancho, J., Sanchez, A.
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Turco, A E, Bambara, L M
(2004). Pregnancy, microchimerism and autoimmunity: an update. Lupus
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[Abstract]
-actin (Sigma, St. Louis), cardiac myosin heavy chain (Chemicon), desmin (Sigma), connexin 43 (Sigma), GATA-4 (Santa Cruz, Santa Cruz, Calif.), MEF2D (Santa Cruz), and nestin (Developmental Studies Hybridoma Bank, Iowa City, Iowa). Smooth-muscle cells were identified by means of antibodies against smooth-muscle 
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