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RESEARCH REPORT |
1 Craniofacial and Skeletal Diseases Branch, Building 30, Room 228, and
2 CIinical Research Core, NIDCR, NIH, Bethesda, MD 20892, USA;
3 School of Dentistry, University of California at San Francisco, USA;
4 Department of Anatomy and Developmental Biology, University College London, UK;
* corresponding author, sshi{at}dir.nidcr.nih.gov
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: stem cell • odontoblasts • dentin • in vivo transplantation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Previous studies have demonstrated that, like osteoblasts, pulp cells express bone markers such as bone sialoprotein, alkaline phosphatase, type I collagen, and osteocalcin (Kuo et al., 1992; Tsukamoto et al., 1992; Nakashima et al., 1994; Butler et al., 1997; Shiba et al., 1998; Buurma et al., 1999; Buchaille et al., 2000). Their differentiation is regulated by various potent regulators of bone formation, including members of the TGFß superfamily and cytokines (Kettunen et al., 1998; Shiba et al., 1998; Onishi et al., 1999). The similarity of the gene expression profiles between DPSCs and precursors of osteoblasts, bone marrow stromal stem cells (BMSSCs), has recently been reported (Shi et al., 2001).
BMSSCs have been defined, by in vitro and in vivo studies, as pluripotential adult stem cells (Prockop, 1997; Bianco et al., 2001). They possess the capacity to differentiate into different kinds of cells such as osteoblasts, chondrocytes, adipocytes, muscle cells, and neural cells (Azizi et al., 1998; Fuchs and Segre, 2000; Bianco et al., 2001). In contrast, DPSCs have not yet been extensively studied in terms of their stem cell properties. Here, we demonstrate that human DPSCs represent a novel adult stem cell population that possesses the properties of high proliferative potential, the capacity of self-renewal, and multi-lineage differentiation.
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MATERIALS & METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Transplantation
Approximately 4.0 x 106 DPSCs or BMSSCs (at 20-30 population doublings) were mixed with 40 mg of hydroxyapatite/tricalcium phosphate (HA/TCP) ceramic powder (Zimmer Inc., Warsaw, IN, USA) and then transplanted subcutaneously into the dorsal surface of 10-week-old immunocompromised beige mice (NIH-bg-nu-xid, Harlan Sprague-Dawley, Indianapolis, IN, USA) as previously described (Krebsbach et al., 1997). These procedures were performed in accordance with specifications of an approved small-animal protocol (NIDCR #00-113).
Anti-human Dentin Sialoprotein Antibody and Immunohistochemistry
Antisera to a portion of the dentin sialoprotein (DSP) fragment of human dentin sialophosphoprotein (DSPP) was produced. Oligonucleotides were constructed to facilitate PCR amplification and subcloning of the Thr132-Asp373 domain of DSPP from a single exon, with human genomic DNA as a template. The PCR product was subcloned into pET-15b bacterial expression vector (NovaGen, Madison, WI, USA), and the induced fusion protein purified on a Ni2+ charged column. The purified product was injected 4 x (~ 0.25 mg each) into New Zealand white rabbits for antisera production. One rabbit (LF-151) produced a serum that showed, by Western analysis, good reactivity against human and bovine, but not murine, dentin extracts.
Unstained sections, deparaffinized with xylene and ethanol, were reacted with primary dentin sialoprotein antibody (1:100 dilution of LF-151). A Zymed broad-spectrum immunoperoxidase kit (Zymed Laboratories, South San Francisco, CA, USA) was used for staining, according to the manufacturer’s protocol.
Histochemistry
The Accustain Trichrome Stain (GOMORI, Sigma HT-10-7, HT-10-9, and HT-10-5-16) and leukocyte acid phosphatase kit (Sigma #387-A) were used to stain paraffin-embedded sections for Trichrome and TRAP (Tartrate Resistant Acid Phosphatase), respectively, according to the manufacturer’s protocols.
Back-scattered Electron Scanning Microscopy (BSE SEM)
Electron microscopy imaging was conducted on carbon-coated, polished block faces of poly-methyl-methacrylate (PMMA) embedded DPSC and BMSSC transplants for identification of the characteristics of the mineralized tissue phases. The samples were imaged in a Zeiss DSM962 digital scanning electron microscope operated at 20 or 30 kV in the back-scattered electron mode with the use of a KE (Toft, Cambs, UK) solid-state back-scatter electron detector.
RT-PCR
Total RNA was prepared from DPSCs, by means of the RNA STAT-60 (TEL-TEST Inc., Friendswood, TX, USA). First-strand cDNA synthesis was performed by means of a first-strand cDNA synthesis kit (GIBCO BRL, Life Technologies, Grand Island, NY, USA) according to the manufacturer’s protocol. The primer set for PCR included: PPAR
2 (sense, 5'-CTCCTATTGACCCAGAAAGC-3', antisense, 5'-GTAGAGCTGAGTCTTCTCAG-3', GenBank accession number XM_003059); LPL (sense, 5'-ATGGAG AGCAAAGCCCTGCTC-3', antisense, 5'-GTTAGGTCCAGCT GGATCGAG-3', GenBank accession number XM_044682); glial fibrillary acid protein (GFAP) (sense, 5'-CTGTTGCCAG AGATGGAGGTT-3', antisense, 5'-TCATCGCTCAGGAGG TCCTT-3', GenBank accession number XM_050159); nestin (sense, 5'-GGCAGCGTTGGAACAGAGGTTGGA-3', antisense, 5'-CTCTAAACTGGAGTGGTCAGGGCT3', GenBank accession number X65964); GAPDH (sense, 5'-AGCCGCATCTT CTTTTGCGTC-3', antisense, 5'-TCATATTTGGCAGGTTTTTCT-3', GenBank accession number M33197). The reactions were pre-incubated in a PCR Express Hybaid thermal cycler (Hybaid, Franklin, MA, USA) at 94°C for 2 min and then cycled 35 times at 94°C/(45 sec), 56°C/(45 sec), 72°C/(60 sec), followed by a final seven-minute extension at 72°C.
In situ Hybridization
Human-specific alu and mouse-specific pf1 sequences labeled with digoxigenin were used as probes for in situ hybridization as previously described (Gronthos et al., 2000). Primers for human alu (sense, 5'-TGGCTCACGCCTGTAATCC-3', and antisense, 5'-TTTTTTGAGACGGAGTCTCGC-3', GenBank accession number A0004024) and mouse pf1 (sense, 5'-CCGGGCAGTG GTGGCGCATGCCTTTAAATCCC-3', and antisense, 5'-GTTTGGTTTTTGAGCAGGGTTCTCTGTGTAGC-3', GenBank accession number X78319) were created.
Flow Cytometric Identification of Human and Mouse Cells
Adherent monolayers of stromal-like cells isolated from three-month-old DPSC transplants were digested with trypsin/EDTA to obtain single cell suspensions. CD-29 purified mouse anti-human or mouse-specific IgG (10 µg/mL) was then added directly to 2 x 105 cells for 1 hr on ice. The cells were then incubated with goat anti-mouse IgM conjugated to FITC (1/50 dilution, DAKO Corp., Carpinteria, CA, USA) for 45 min on ice. After being washed twice in PBS, the cells were analyzed with the use of a FACSCalibur flow cytometer. Positive expression was defined as the level of fluorescence greater than 99% of the corresponding isotype-matched control antibodies.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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). Equivalent BMSSC transplants were composed of ectopic bone, undergoing normal turnover as demonstrated by the presence of osteoclasts at the regenerated bone surfaces, and active hematopoiesis and adipogenesis, none of which was present in the dentin-pulp complex of the DPSC transplants (Figs. 1B, 1D). In addition, back-scattered electron scanning microscopy showed that DPSCs formed a mineralized matrix with a globular, calcospheritic mineralization pattern similar to that of primary dentin (Fig. 1E), and distinct from that seen in the ectopic lamellar bone observed in BMSSC transplants (Fig. 1F).
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), based on FACS analysis with the use of either human- or mouse-specific antibodies against a cell-surface marker CD29. The majority of the isolated stromal-like cells were further shown to be positive for a human-specific alu DNA probe, with a minor population of cells expressing the mouse-specific pf1 DNA probe by in situ hybridization (Figs. 2C, 2D). After expansion in vitro, human cells were re-transplanted into immunocompromised mice. The secondary transplants yielded human alu-positive odontoblasts that gave rise to a dentin-pulp-like complex containing organized collagen fibers detected by Trichrome staining (Figs. 2E, 2F). Importantly, the regenerated dentin was immunoreactive for human DSP antibody (Fig. 2G). These findings indicated that human DPSCs satisfy one important stem cell attribute in their ability to selfrenew in vivo.
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). This correlated with an up-regulation in the expression of two adipocyte-specific transcripts, PPAR2 and lipoprotein lipase, detected by RT-PCR (Fig. 3B). Furthermore, DPSCs were found to express nestin and glial fibrillary acid protein (GFAP), markers of neural precursors and glial cells, respectively, at both the mRNA and protein levels (Figs. 3C-3G). These results suggested that DPSCs are similar to other stem cell populations, such as BMSSCs, in possessing the ability to develop into developmentally diverse phenotypes.
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). This indicates that the majority of clonogenic DPSCs do not grow extensively ex vivo and that only a small percentage of clonogenic DPSCs (20%) will ultimately represent the cell population at later PDs. Interestingly, when 12 single-colony-derived DPSC strains with the ability to proliferate over 20 population doublings were transplanted into immunocompromised mice, the majority (two-thirds) demonstrated a potential equivalent to that of multi-colony-derived DPSCs in being able to generate abundant ectopic dentin on and in the HA/TCP carrier (Fig. 4B). However, the remaining third of the single-colony-derived DPSC strains formed only a moderate to low amount of dentin when compared with multi-colony-derived DPSCs (Fig. 4C). The dentin-pulp-like complex formed by each individual colony, however, demonstrated the same structural properties as its parental clone. The regenerated dentin and normal dentin were positive for human DSP, as shown by immunohistochemical staining (Figs. 4D, 4E). Under the same immunohistochemical staining conditions, BMSSC transplants were negative for human DSP staining (data not shown). These results imply that DPSCs may contain subpopulations of cells with different proliferative rates and developmental potentials, a property similar to that of BMSSCs. Human DPSCs were also identified in the pulp-like connective tissue, even 5 mos post-transplantation (Appendix Fig., www.dentalresearch.org), indicating that this population of cells might be the ones responsible for the self-renewal.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Recently, it was reported that DSPP may also be expressed in bone, albeit at low levels. In the present study, we found that an antibody specific to DSP protein localized to the peritubular dentin area and to the odontoblast layer in sections of human teeth by immunohistochemical staining. This DSP antibody may be not sensitive enough to detect DSP antigen in BMSSC transplants, if in fact there is any.
Based on current information, we suggest that DPSCs may have a broader capacity for differentiation than originally thought. Although it seems probable that several different cell types reside in pulp tissue, adipocytes are not a normal cellular component in dental pulp. We initially reported that DPSCs were unable to develop adipocytes following treatment with the glucocorticoid, dexamethasone, as is seen in dexamethasone-induced BMSSCs (Gronthos et al., 2000). However, we now report that a more potent adipogenenic-inductive culture medium (Gimble et al., 1995) can induce DPSCs to form characteristic oil red O-positive lipid-containing adipocytes. This phenotypic conversion was also correlated with the expression of the early adipogenic master gene PPAR2 and the late marker lipoprotein lipase. Recently, neuronal stem cells were reported to be isolated from dermis, a tissue that contains abundant nerve fibers (Toma et al., 2001). Dental pulp also contains prominent nerve fibers, which penetrate the dentin tubules. Previous reports provided evidence that nestin and GFAP could be detected in pulp cells (Davidson, 1994; About et al., 2000), and pulp cells might even be capable of producing a variety of neurotrophins (Nosrat et al., 2001).
Analysis of dentin formation in vivo by single-colony-derived strains of human DPSCs showed that most of the colonies (80%) failed to proliferate beyond 20 population doublings (PD). Thus, these strains cannot be expanded ex vivo to produce sufficient numbers of cells to analyze all their developmental potentials in vivo. We therefore utilized those single-colony-derived DPSC strains which had the potential to proliferate at least over 20 PD. Multi-colony-derived DPSCs of 20 to 30 PD were consistent in their capacity to proliferate in vitro and to regenerate dentin in vivo. Based on our results, only 67% (8 out of 12) of the highly proliferative single-colony-derived DPSC strains were capable of forming the abundant amounts of dentin comparable with the parental multi-colony-derived cultures. Analysis of the dentin matrix formed by single-colony-derived strains demonstrated a mineralized dentin matrix, containing organized collagen fibers, similar to that formed by multi-colony-derived DPSCs. Collectively, these studies suggest a hierarchy of progenitors in adult dental pulp, including a minor population of self-renewing, highly proliferative, multi-potent stem cells, among a larger compartment of perhaps more committed progenitors. The concept of a hierarchy of cellular differentiation has previously been described for other stem cell populations, such as BMSSCs (Kuznetsov et al., 1997). In conclusion, we provide compelling evidence to show that DSPCs belong to a novel population of post-natal somatic stem cells. These cells can serve as a model for the study of adult stem cell differentiation in vitro and tissue regeneration in vivo.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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A supplemental appendix to this article is published electronically only at http://www.dentalresearch.org
Received December 27, 2001; Last revision April 26, 2002; Accepted June 5, 2002
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