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TISSUE-SPECIFIC STEM CELLS |
aDepartment of Cell Biology, New York University School of Medicine, New York, New York, USA;
bDepartment of Science, Borough of Manhattan Community College, New York, New York, USA;
cDivision of Immunology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa;
dDepartment of Urology, New York University School of Medicine, New York, New York, USA;
eKaplan Cancer Center, New York University School of Medicine, New York, New York, USA
Key Words. Proximal prostate stem cells • Ductal axis • Androgen sensitivity
Correspondence: E. Lynette Wilson, Ph.D., Department of Cell Biology, MSB 634, NYU School of Medicine, 550 First Avenue, New York, New York 10016, USA. Telephone: 212-263-7684; Fax: 212-263-8139; e-mail: wilsoe01{at}popmail.med.nyu.edu
Received on November 23, 2005;
accepted for publication on April 21, 2006.
First published online in STEM CELLS EXPRESS April 27, 2006.
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ABSTRACT |
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INTRODUCTION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionSummaryDisclosuresAcknowledgmentsReferences |
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We therefore isolated cells from different regions of prostatic ducts removed from donor androgen-replete or castrated animals and examined their ability to regenerate prostatic tissue in recipient androgen-replete as well as in androgen-ablated and reconstituted animals. This was done using an in vivo prostate reconstitution assay in which combinations of prostate cells and embryonic urogenital sinus mesenchyme (UGM) (inductive mesenchyme for prostatic tissue) [13–15] are inserted under the renal capsule (RC) of recipient animals, where they form prostatic tissue. We find that cells isolated from the intermediate and distal regions do not survive androgen ablation whereas those from the proximal region and the urethra are able to withstand prolonged androgen deprivation, indicating the presence of cells with stem cell properties in these areas. Additionally, we show for the first time that primitive proximal prostate cells, which regenerate functional prostatic tissue, are programmed to re-establish a proximal-distal ductal axis when inserted under the RC. Similar to the primitive cells in the intact prostate, the cells with the highest regenerative capacity are also found in the proximal region of ducts in the sub-RC prostatic tissue and can be passaged through four generations of sub-RC grafts.
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MATERIALS AND METHODS |
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Preparation of Dissociated Prostate and Urethra Cells
Six-week-old C57BL/6 mice were sacrificed, and the urogenital tract was removed en bloc and transferred in Hanks' balanced salt solution (Mediatech, Inc., Herndon, VA, http://www.cellgro.com). The dorsal prostate (DP) was removed and dissected under a dissecting microscope in the presence of 0.5% collagenase (1.3 units/mg; Sigma-Aldrich, St. Louis, http://www.sigmaaldrich.com) [16]. The proximal, intermediate, and distal regions (Fig. 1AA) were excised, minced finely, and incubated in collagenase for 60 minutes followed by digestion in 0.25% trypsin (DIFCO Bacto Trypsin 250; BD Biosciences, Sparks, MD, http://www.bd.com) for an additional 10 minutes at 37°C [4]. A portion of the urethra was removed (Fig. 1A) and was similarly digested. Cells were passed through a 40-µm nylon mesh (Becton, Dickinson and Company, Franklin Lakes, NJ, http://www.bd.com), and viability was determined by trypan blue exclusion.
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Implantation of Grafts Under the RC
The grafts were implanted under the RC of intact or castrated athymic male mice [13] (tutorial for technique: http://mmmary.nih.gov/tools/Cunha001/index.html). Cells from the urethra or different regions of ducts (105 unless otherwise indicated) were combined with UGM cells (2.5 x 105) and resuspended in 15 µl of type 1 collagen (BD 354236; BD Biosciences, Bedford, MA, http://www.bdbiosciences.com). The collagen was allowed to gel at 37°C for 15 minutes after which the grafts were inserted under the RC. Where indicated, androgens were administered by the subcutaneous implantation of testosterone pellets (5 mg; Innovative Research of America, Sarasota, FL, http://www.innovrsrch.com). Each experiment contained a set of grafts of UGM alone (3.5 x 105 cells) to ensure that tissue growth did not result from contaminating urogenital sinus epithelial cells. In addition, some experiments were done using prostate cells isolated from GFP transgenic mice (C57BL/6-TgN; The Jackson Laboratory) to ensure that tissue growth resulted from donor GFP-expressing cells and not contaminating epithelial cells in the UGM preparation (supplemental online Fig. 3). Grafts were harvested after 8 weeks of in vivo growth, weighed, and used for immunohistochemical examination.
Passage of Undissected Recombinant Tissue (All Regions) In Vivo
The ability of proximal and distal regions of primary prostate cells to undergo multiple rounds of growth was assessed by serial in vivo passaging of recombinant tissue. Cells isolated from proximal and distal regions of prostatic ducts (1 x 105) were combined with UGM (2.5 x 105 cells) and implanted under the RC of intact 6-week-old male athymic nude mice. After 8 weeks, the recipient mice were sacrificed, and grafts from either proximal or distal cells (P1) (Fig. 2A) were retrieved and weighed. Grafts arising from either proximal or distal cells were minced finely, digested in collagenase (see above), and trypan blue-excluding cells were enumerated. These cells (1 x 105 cells) were combined with UGM (2.5 x 105 cells) and implanted into recipient mice to produce a "second passage (P2)" graft (Fig. 2A). This protocol was repeated until no tissue growth was noted.
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-smooth muscle actin (A2547; Sigma-Aldrich) were directly coupled to horseradish peroxidase (HRP) using Dako's Envision + system (Dako, Carpinteria, CA, http://www.dako.com) and detected using DAB (3,3' diaminobenzidine) as the substrate. Rabbit polyclonal antibodies that are specific to Nkx3.1 [19] and to secretions of the DP were a gift of Dr. C. Abate-Shen (Robert Wood Johnson Medical School, Piscataway, NJ; M. Kim, M.M. Shen, and C. Abate-Shen, personal communication) [4]. Cytokeratin-5 was visualized using rabbit polyclonal antibodies (PRB-160P; Covance, Princeton, NJ, http://www.covance.com) and appropriate HRP-linked secondary antibodies (Amersham Biosciences, Piscataway, NJ, http://www.amersham.com). GFP was visualized using rabbit polyclonal antibodies (46–0092; Invitrogen, Carlsbad, CA, http://www.invitrogen.com) and the ABC staining kit (Vector Laboratories, Burlingame, CA, http://www.vectorlabs.com). Androgen receptors were visualized using rabbit polyclonal antibodies (sc-816; Santa Cruz Biotechnology, Inc., Santa Cruz, CA, http://www.scbt.com) and the ABC staining kit (Vector Laboratories). The specificity of staining was ascertained on sections using nonimmune serum or immunoglobulin G in place of primary antibodies. Sections were counterstained with hematoxylin.
Isolation of 6 Integrin Expressing Cells
Samples were enriched for 6 integrin (CD49f)-expressing cells by immunomagnetic separation using antibodies to this antigen (BD 555734; BD Biosciences) and magnetically activated cell sorter (MACS) microbeads, magnetic columns, and the MiniMACS system (Miltenyi Biotec, Auburn, CA, http://www.miltenyibiotec.com).
Cell Preparation and Fluorescence-Activated Cell Sorting Analysis
Prostatic cell digests obtained from either the proximal region or the remaining (intermediate and distal) regions were resuspended in fluorescence-activated cell sorting (FACS) buffer (phosphate-buffered saline containing bovine serum albumin [0.1%], sodium azide [0.01%], and aprotinin [20 µg/ml]) [5]. For analysis of viable 6 integrin-expressing cells, the dye 7-aminoactinomycin D (1 µg/ml) was added 5 minutes prior to FACS acquisition to cells treated with antibodies to 6 integrin conjugated to fluorescein isothiocyanate (FITC). Analysis of the co-expression of Sca-1, 6 integrin, and Bcl-2 was determined in permeabilized paraformaldehyde-fixed cells using antibodies to 6 integrin conjugated to FITC (BD 555735; BD Biosciences) in conjunction with antibodies to Bcl-2 conjugated to phycoerythrin (PE) (sc-7382 PE; Santa Cruz Biotechnology, Inc.) and antibodies to Sca-1 conjugated to biotin (MSCA15; Caltag Laboratories, Burlingame, CA, http://www.caltag.com) followed by streptavidin APC (SA1005; Caltag Laboratories) [5]. Cells were analyzed on a FACSCalibur flow cytometer (Becton, Dickinson and Company), using CellQuest software (Becton, Dickinson and Company).
Statistical Analysis
The results are depicted as the means and SDs of each set of data. Comparisons between groups were made using the two-tailed, paired Student's t test, or the nonparametric two-tailed Mann-Whitney U test. A p value of < .05 was considered statistically significant.
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RESULTS |
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Each experiment contained grafts consisting of UGM alone to ensure that tissue growth did not result from contaminating urogenital sinus epithelial cells. The UGM grafts were weighed and examined microscopically to exclude urogenital sinus epithelial contamination. The average weight of UGM tissue alone was 8.3 ± 2.2 mg. In addition, some experiments were done using prostate cells isolated from GFP transgenic mice to ensure that tissue growth resulted from donor GFP-expressing cells and not contaminating epithelial cells in the UGM preparation (supplemental online Fig. 3).
To determine the minimum number of cells capable of forming prostatic tissue, the sub-RC growth of varying numbers of proximal and distal cells (105 to 4 x 102 cells) was determined (supplemental online Fig. 4). The proximal region contained cells with 50-fold greater regenerative capacity than those from the distal region as 400 proximal cells formed prostatic tissue whereas 20,000 distal cells were required for tissue growth. A linear relationship between the tissue mass and inoculum dose was noted between 400 and 105 cells (supplemental online Fig. 4). The size of the UGM inoculum also affected tissue size with a linear relationship in its ability to support prostate tissue growth between 2.5 x 104 and 2.5 x 105 UGM cells (data not shown).
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Cells from the Proximal Region and the Urethra Survive Prolonged Androgen Deprivation
Because prostatic tissue can regenerate after androgen withdrawal and replenishment, we reasoned that cells from regions most enriched in androgen-independent cells having regenerative potential would survive prolonged androgen deprivation and would regenerate prostatic tissue to a greater extent than cells isolated from regions that consisted mainly of transit-amplifying cells. Transit-amplifying cells are considered to be progenitor cells that are capable of division and that represent a post-stem cell compartment.
To determine the sensitivity to androgens, donor cells isolated from different regions of ducts of androgen-replete animals were implanted under the RC of (a) androgen-replete recipients and harvested after 8 weeks, (b) castrated recipients and harvested after 16 weeks, and (c) castrated recipients and harvested after 8 weeks of androgen deprivation followed by 8 weeks of androgen supplementation (Fig. 4A). Each group received donor cells isolated from one of the following: all regions of ducts, the proximal, intermediate, or distal region, or the urethra (Fig. 1A). Very little growth was noted when cells from any region were implanted in castrated recipients (Fig. 4B, center bar in each group). Cells isolated from both the proximal region and the urethra maintained full regenerative capacity through 8 weeks of androgen deprivation; the amount of prostatic tissue that was formed after subsequent exposure to androgens was comparable with that noted when cells from the proximal region or the urethra were implanted in androgen-replete animals (Fig. 4B, supplemental online Fig. 5). In contrast, the ability of cells isolated from the intermediate and distal regions to regenerate prostatic tissue was severely compromised by androgen deprivation (Fig. 4B, supplemental online Fig. 5), indicating that these regions contained cells that require androgen for survival. Intermediate or distal cells formed more tissue in intact animals (65 ± 26 mg or 25 ± 19 mg, respectively) compared with animals maintained in an androgen-deficient state for 8 weeks and subsequently exposed to androgens for an additional 8 weeks (5 ± 3 mg or 3 ± 1 mg respectively; p < .001; Fig. 4B, supplemental online Fig. 5). Cells isolated from all regions of the prostate (Fig. 1A) could regenerate more prostatic tissue (Fig. 4B, supplemental online Fig. 5) than could intermediate or distal cells. This is likely due to the proximal cells included in this fraction. These data indicate that cells in the proximal region can survive prolonged periods of androgen deprivation and retain full regenerative potential and that urethral cells have similar properties.
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Castration results in the involution of the gland and the loss of significant numbers of cells primarily from distal regions, with the proximal region being least affected [1, 2]. We therefore compared the phenotype and growth potential of cells isolated from the proximal and remaining regions of ducts from androgen-replete and castrated animals to determine whether cells with primitive regenerative features were enriched in the remaining regions of ducts after involution.
We have previously shown that cells coexpressing the antigens Sca-1, 6 integrin, and Bcl-2 are concentrated in the proximal region of ducts [5]. We therefore determined the coexpression of these antigens on cells in different ductal regions in androgen-replete and castrated animals to ascertain whether their incidence was altered by involution of the gland (Fig. 5A). Castration resulted in a 3.4-fold increase (p < .04) in cells that coexpressed these antigens in the remaining regions of ducts, whereas similar numbers of cells in the proximal region of intact and castrated animals coexpressed these antigens.
We next compared the proliferative potential of cells isolated from different regions of ducts from both androgen-replete and castrated animals. Cells isolated from the remaining regions of ducts of castrated animals formed 5.3-fold more sub-RC tissue than did cells isolated from the remaining regions of ducts of intact animals (p < .001), whereas cells isolated from the proximal region from intact and castrated animals formed similar amounts of tissue (Fig. 5B). This indicates that involution of the gland is accompanied by the enrichment of those cells with proliferative potential in the remaining regions of ducts, whereas castration does not affect the proportion of cells capable of forming prostatic tissue in the proximal region. These data show that castration enriches for cells with a primitive phenotype in the remaining region of ducts, indicating that the more mature cells die during involution. The proportion of primitive cells in the proximal region is unaffected by androgen levels, indicating that cells in this region survive androgen ablation.
Cells from the Proximal Region Can Be Serially Passaged In Vivo
Passage of cells isolated from undissected recombinant tissue (i.e., all regions). Because stem cells have high regenerative potential, we determined whether the RC tissue obtained after implantation of proximal cells could be serially passaged in vivo more frequently than tissue arising from distal cells. Cells (105) were isolated from the proximal and distal regions of primary prostates and implanted under the RC (Fig. 2A). Prostatic tissue obtained from proximal and distal cell sub-RC implants was weighed and digested. Cells (105) from each of these digests were combined with UGM and re-implanted under the RC of a second animal (P2). This process was repeated until no prostatic tissue growth was noted (Fig. 2A, 2B). Cells from the proximal region can be serially passaged four times, whereas distal cells can be passaged twice. In addition, as noted previously in primary implants (Fig. 1), cells isolated from the proximal region formed larger amounts of prostatic tissue at each consecutive passage than did cells isolated from the distal region, indicating that proximal cells were capable of more extensive division than distal cells.
Passage of cells isolated from the proximal region of recombinant tissue. We wished to determine whether the sub-RC prostatic tissue formed an "organ" that maintained a physiologically distinct proximal-distal ductal axis similar to that observed in the prostate and whether cells isolated from different regions of the sub-RC graft displayed similar disparate growth properties to that noted in primary prostatic ducts. Cells were therefore isolated from proximal and distal ductal regions of the primary prostate (Fig. 3A, 3B) and implanted under the RC. Microdissection of the sub-RC tissue mass obtained from proximal cells (Fig. 3A, 3C) revealed an interconnected series of ducts consisting of proximal and distal regions very similar to that obtained from the primary prostate (Fig. 3B). Quite remarkably, when these ducts were dissected into proximal and distal regions and isolated cells were reimplanted under the RC, the cells from the proximal region once again formed large amounts of prostatic tissue (228 ± 83 mg) compared with cells obtained from the distal region (5 ± 4 mg; p < .02; Fig. 3A, 3D, P2). The tissue obtained from P2 proximal cells also had a visible proximal-distal ductal axis and was similarly dissected and reimplanted. Proximal cells again formed more (76 ± 23 mg) prostatic tissue than did distal cells (49 ± 19 mg; P3, p < .04). The tissue obtained from P3 proximal cells was again dissected and reimplanted. A small amount of sub-RC prostatic tissue growth was noted in two (9.3 ± 1.6 mg) out of six proximal cell implants (P4).
These data indicate that primitive proximal cells are programmed to re-establish a proximal-distal ductal axis under the RC (Fig. 3C) and have extensive regenerative capacity, as they can be passaged through four generations of sub-RC grafts. Cells isolated from the proximal region of successive grafts form considerably more sub-RC tissue (Fig. 3; 228 mg P2, 76 mg P3) than those isolated from similar passages from the entire graft (Fig. 2; all regions, 78 mg P2, 2 mg P3). This confirms that the proximal region of sub-RC tissue is similar to the proximal region of a primary prostate gland because it is also enriched in primitive cells with high regenerative capacity.
6 Integrin-Expressing Proximal Cells Have High In Vivo Proliferative Potential
6 integrin is present on primitive cells from a number of origins [24–29], including the prostate [5], and the gene for this antigen was the only common gene identified in a study using transcriptional profiling to identify genes expressed by stem cells of embryonic, neural, hematopoietic, and retinal origin [30]. To determine whether cells expressing this antigen were enriched after castration and to ascertain whether 6 integrin-expressing cells had greater regenerative capacity than cells not expressing this antigen, we performed two sets of experiments. We first determined expression of this antigen on proximal and remaining cells from androgen-replete and castrated animals. The proximal region of intact animals contained 2.8-fold (p < .002) more 6 integrin-expressing cells than the remaining regions of ducts (Fig. 6A). Castration resulted in an increase in 6 integrin-expressing cells in the remaining ductal regions (from 14.2% ± 5.6% to 25.1% ± 2.4%; p < .02) without affecting the incidence of these cells in the proximal region, indicating that involution of the gland was accompanied by an enrichment in 6 integrin-expressing cells. We next isolated cells expressing 6 integrin from the proximal region and determined their regenerative potential in vivo. Cells enriched for 6 integrin expression formed 4.3-fold more prostatic tissue (57 ± 48 mg) than did cells depleted of this antigen (13 ± 14 mg; p < .002, Fig. 6B), indicating that 6 integrin-expressing cells have greater regenerative potential than those cells lacking this antigen.
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DISCUSSION |
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-reductase [31], the differences in sensitivity to androgens are not due to regional variations in expression of these molecules. Although we and others [32] show that the sizes of the grafts are dependent on the numbers of epithelial cells used in the assay, some [15] have reported that the amount of acinar growth was dependent on the mesenchymal tissue and not the epithelial component. We are uncertain of the explanation for these differences. A possible explanation could be that we used digests of prostate cells obtained from adult animals whereas Chung and Cunha [15] used fragments of epithelium of embryonic origin.
We also show that, in the remaining regions of ducts, castration results in the enrichment of primitive cells that are capable of forming prostatic tissue. Cells removed from the remaining regions of ducts of an involuted prostate formed more tissue under the RC than did cells isolated from these regions of an androgen-replete prostate. Castration results in the loss of large numbers of epithelial cells from the distal regions of ducts [1, 2]. We show that this is accompanied by an increase in the proportion of cells in these regions that coexpress three antigens (Sca-1, 6 integrin, and Bcl-2) shown to be expressed by primitive prostate cells [5]. The remaining regions of ducts of intact animals have very few of these primitive cells. These results support the idea that the cells lost as a result of castration are differentiated nonregenerative cells. It is interesting that isolated cells removed from remaining regions of ducts and placed in castrated recipients for 2 months followed by androgen administration could not reconstitute prostatic tissue under the RC whereas cells isolated from the remaining ductal regions of an involuted prostate removed from an androgen-deprived animal can regenerate prostatic tissue. This discrepancy may be due to the enrichment of primitive cells in the remaining ductal regions that follows castration and involution as this process results in the loss of differentiated cells. Thus, a larger number of primitive cells would be present in the remaining regions of castrated prostates than in the remaining regions of androgen-replete prostates.
We also show that primitive cells in the proximal region are programmed to regenerate a proximal-distal ductal axis through consecutive passages in a prostate reconstitution assay. The most definitive test of stem cell function is their ability to reconstitute an organ. Serially transplanted bone marrow can reconstitute lethally irradiated mice [33, 34], and the number of successful serial transfers is dependent on the size of the grafts and the time intervals between transfers [35].
The appearance of the dissected sub-RC tissue was remarkably similar to that noted in an intact prostate gland (Fig. 3B, 3C), and primitive cells were concentrated in the proximal regions of both the intact gland and the sub-RC tissue. This indicates that primitive prostate cells are programmed to regenerate an organ with regional differences in regenerative capacity. Isolated cells from the proximal regions of sequential grafts could be passaged four times before senescence and formed large amounts of prostatic tissue (228 ± 83 mg) that greatly exceeded the size of a primary prostate gland (11 ± 1 mg). This indicates that primitive cells in the proximal region of the sub-RC grafts have considerable regenerative capacity. It is not surprising that primitive proximal cells cannot be passaged indefinitely; experimental evidence indicates that hematopoietic stem cells show signs of aging and have a limited functional lifespan [36]. This is likely to be an important discriminator between healthy stem and tumor stem cells.
6 Integrin is the only common protein expressed by stem cells of a number of origins and is present on the primitive cells of different tissues [5, 24–30]. We show that in the prostate the expression of 6 integrin alone is also indicative of a primitive phenotype as the proportion of cells expressing this antigen in the remaining regions of ducts is increased after castration. In addition, proximal cells enriched for 6 integrin expression have 4.3-fold greater proliferative potential than those depleted of this antigen, indicating that 6 integrin expression identifies cells with enhanced regenerative potential in vivo as has been recently shown for cells expressing Sca-1 [5, 6]. Putative human prostate stem cells have also been shown to express high levels of another member of the integrin family, namely 2 integrin [37].
Stem cells generally reside in specialized niches that form a microenvironment that maintains their primitive phenotype. The proximal region of ducts provides a protective niche for prostatic stem cells which may permit them to survive in the absence of androgen. This region is least affected by castration in terms of apoptosis and cell loss [1, 2], as indicated by the similar incidence of cells in this region that coexpress Sca-1, 6 integrin, and Bcl-2 in androgen-replete and castrated animals. The proximal region also has the highest levels of telomerase [38], which is associated with germinative compartments of many self-renewing tissues [39, 40]. The cells in the proximal stem cell niche are kept quiescent by high levels of TGF-ß signaling in this region (compared with low levels of signaling in distal regions), and they are protected from the TGF-ß-mediated apoptosis that follows androgen withdrawal by high levels of Bcl-2 expressed by cells in the proximal region [3].
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SUMMARY |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionSummaryDisclosuresAcknowledgmentsReferences |
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DISCLOSURES |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionSummaryDisclosuresAcknowledgmentsReferences |
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ACKNOWLEDGMENTS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionSummaryDisclosuresAcknowledgmentsReferences |
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REFERENCES |
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