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Odontogenic differentiation of adipose-derived stem cells for tooth regeneration: necessity, possibility, and strategy
Medical Hypotheses (2008) 70, 540–542
http://intl.elsevierhealth.com/journals/mehy
Odontogenic differentiation of adipose-derived stem cells for tooth regeneration: necessity, possibility, and strategy Wei Jing, Ling Wu, Yunfeng Lin, Lei Liu, Wei Tang, Weidong Tian
*
Department of Oral and Maxillofacial Surgery, West China College of Stomatology, Sichuan University, No. 14, 3rd Sec., Ren Min Nan Road, Sichuan Province, Chengdu 610041, China Received 11 June 2007; accepted 11 July 2007
Summary Tooth regeneration using tissue engineering concepts is a promising biological approach to solving problems of tooth loss in elderly patients. The seeding cells, however, for tooth regeneration such as odontoblasts from dental germ, stem cells from dental pulp and deciduous teeth, and ectomesenchymal cells from the first branchial arch are difficult, even impossible to harvest in clinic. Bone marrow mesenchymal stem cells have odontogenic capacity, but their differentiation abilities significantly decrease with the increasing age of the donors. Therefore, the cells mentioned above are not practical in the clinical application of tooth regeneration in the old. Adipose derived stem cells have many clinical advantages over bone marrow mesenchymal stem cells, and their differentiation potential can be maintained with aging. Here we propose the hypothesis that adipose derived stem cells could be induced into odontogenic lineage and might be used as suitable seeding cells for tooth regeneration to replace the lost tooth of elderly patients. c 2007 Elsevier Ltd. All rights reserved.
Introduction and hypothesis Tooth loss due to decay or periodontal disease is a common occurrence in old people. Routine clinical treatments for tooth replacement, e.g., synthetic materials, may elicit an immune-induced host rejection response. Tooth regeneration using tissue engineering concepts is a promising biological approach that aims to regenerate natural tooth-like mineral tissues in terms of histology, morphology and function. Odontoblasts from dental germ, stem * Corresponding author. Tel.: +86 028 85503406. E-mail address: [email protected] (W. Tian).
cells from dental pulp and deciduous teeth, and ectomesenchymal cells from the first branchial arch showed odontogenic differentiation potential in basic research, whereas these cells are not practical to harvest in clinic [1–4]. Likewise, bone marrow mesenchymal stem cells (BMSCs) are not ideal seeding cells for old patients because these cells remarkably lose their differentiation ability with the donor age increasing [5]. In recent studies, adipose derived stem cells (ASCs) showed excellent pluripotency potential and many advantages over BMSCs [6–9], and their osteogenic potential can be maintained with aging [10,11]. Thus, ASCs are good alternatives for BMSCs used in hard tissue
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.07.010
Odontogenic differentiation of adipose-derived stem cells for tooth regeneration engineering. Therefore, we hypothesize that ASCs might probably have the ability to be induced into odontogenic lineage and could be a suitable source of cells for tooth regeneration especially in elderly patients.
Evaluation of the hypothesis Necessity of tooth regeneration using ASCs A key challenge in tooth regeneration is to find appropriate seeding cells that can be used in the clinic. The odontoblasts, as essential precursors during tooth development, appear to be an ideal source of seeding cells in tooth regeneration. Unfortunately, odontoblasts are mitotically mature and hard to separate and culture in vitro, which hinder their use for clinical purpose [1]. Stem cells derived from postnatal dental pulp and exfoliated deciduous teeth have been used for seeding [2,3], and the first branchial arch derived ectomesenchymal cells were proved able to differentiate into odontoblast-like cells in our previous study [4]. Whereas, obtaining these cells in the clinic is difficult, maybe even impossible. The multi-differentiation potential especially the osteogenic ability of adult stem cells such as BMSCs and ASCs has attracted increasing attention in hard tissue regenerative medicine. Recently, BMSCs were employed in tooth regeneration studies by different groups including ours, and showed capacities of odontogenic differentiation and tooth-like tissue formation [12–14]. It is well known, however, that the differentiation potential of BMSCs significantly decreases as donor age increases [5]. Moreover, the BMSCs used in the previous studies on tooth regeneration were from juvenile or young donors but not from old ones [12–14]. For these reasons, there is doubt that BMSCs are suitable for research and application of tooth regeneration in the elderly population. When contemplating clinical strategies, the ease of harvest, large number of cells and rapid in vitro expansion are attractive advantages of ASCs over BMSCs. Most important of all, it was shown both in vitro and in vivo that osteogenic potential of ASCs can be maintained with aging, which supports the potential of using ASCs as seeding cells for hard tissue engineering in an aging population [10,11].
The possibility that ASCs differentiate into odontogenic lineage Tooth develop from the sequential and reciprocal interactions between embryonic oral epithelial
541
cells and ectomesenchymal cells [15,16]. Many molecular and cellular studies have indicated that the fetal oral epithelium provides direct signals for the initiation and morphology confirmation during tooth development [17]. When these signals are received by ectomesenchymal cells, the biological process of odontogenesis is initiated [18]. In previous researches regarding tooth regeneration, odontogenesis could be induced by a combination of oral epithelium and BMSCs, demonstrating that nondental adult mesenchymal stem cells have sufficient plasticity to react with signals secreted by the oral epithelium [12,14]. ASCs, as a source of adult stem cells, not only have the potential to differentiate into cells of mesodermal origin, but have the ability to differentiate into cells of nonmesodermal origin, such as neurons, endocrine pancreatic cells, hepatocytes, endothelial cells, and cardiomyocytes [6,8]. Moreover, recent studies suggested that ASCs and BMSCs displayed similar expression profiles and multi-differentiation abilities [19,20]. Therefore, ASCs could probably have the capacity to be induced into odontogenic lineage in specific culture system.
Our strategy We have demonstrated both in vitro and in vivo that BMSCs can differentiate into functional odontoblast-like cells when co-cultured with embryonic oral epithelial cells and transplanted into the renal capsule of the SD rat [12]. This co-culture system and transplantation system can also be used in the experiments to test the hypothesis above. For in vitro test, its worth mentioned that ASCs should be labeled, for example, by the constructed adenovirus vector AD-GFP, before co-culture, so that they can be sorted by flow cytometry after co-culture and analyzed for their differentiation characteristics. For in vivo test, different types of cells should be centrifuged sequentially to ensure that the pellet of ASCs be overlayed with the embryonic oral epithelial cells to mimic the epithelium–mesenchyme interactions of tooth development in vivo.
Conclusion The replacement of lost teeth by whole tooth regeneration is one of the major goals of dental technology. ASCs have clinical advantages over other seeding cells that have been used in tooth regeneration research. If the hypothesis discussed here is true, ASCs will be a novel source of cells for tooth regeneration, and this will highlight the
542
Jing et al.
possibility of tooth replacement in elderly patients using tissue engineering approaches. [10]
References
[11]
[1] Linde A, Goldberg M. Dentinogenesis. Crit Rev Oral Biol Med 1993;4:679–728. [2] Gronthos S, Brahim J, Li W, et al. Stem cell properties of human dental pulp stem cells. J Dent Res 2002;81:531–5. [3] Miura M, Gronthos S, Zhao M, et al. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci USA 2003;100:5807–12. [4] Yan Z, Lin Y, Jiao X, et al. Characterization of ectomesenchymal cells isolated from the first branchial arch during multilineage differentiation. Cells Tissues Organs 2006;183:123–32. [5] Stenderup K, Justesen J, Clausen C, Kassem M. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone 2003;33:919–26. [6] Schaffler A, Buchler C. Concise review: adipose tissuederived stromal cells-basic and clinical implications for novel cell-based therapies. Stem Cells 2007;25:818–27. [7] Wu L, Wu Y, Lin Y, et al. Osteogenic differentiation of adipose derived stem cells promoted by overexpression of osterix. Mol Cell Biochem 2007;301:83–92. [8] Lin Y, Liu L, Li Z, et al. Pluripotency potential of human adipose-derived stem cells marked with exogenous green fluorescent protein. Mol Cell Biochem 2006;291:1–10. [9] Lin Y, Luo E, Chen X, et al. Molecular and cellular characterization during chondrogenic differentiation of
[12]
[13]
[14]
[15] [16]
[17] [18]
[19]
[20]
adipose tissue-derived stromal cells in vitro and cartilage formation in vivo. J Cell Mol Med 2005;9:929–39. Cowan CM, Shi YY, Aalami OO, et al. Adipose-derived adult stromal cells heal critical-size mouse calvarial defects. Nat Biotechnol 2004;22:560–7. Shi YY, Nacamuli RP, Salim A, Longaker MT. The osteogenic potential of adipose-derived mesenchymal cells is maintained with aging. Plast Reconstr Surg 2005;116:1686–96. Li ZY, Chen L, Liu L, Lin YF, Li SW, Tian WD. Odontogenic potential of bone marrow mesenchymal stem cells. J Oral Maxillofac Surg 2007;65:494–500. Hu B, Unda F, Bopp-Kuchler S, et al. Bone marrow cells can give rise to ameloblast-like cells. J Dent Res 2006;85: 416–21. Ohazama A, Modino SA, Miletich I, Sharpe PT. Stem-cellbased tissue engineering of murine teeth. J Dent Res 2004;83:518–22. Thesleff I. Epithelial-mesenchymal signalling regulating tooth morphogenesis. J Cell Sci 2003;116:1647–8. Jing W, Xuan M, Lin Y, et al. Odontogenic tumours: a retrospective study of 1642 cases in a Chinese population. Int J Oral Maxillofac Surg 2007;36:20–5. Thesleff I. Developmental biology and building a tooth. Quintessence Int 2003;34:613–20. Ferguson CA, Tucker AS, Sharpe PT. Temporospatial cell interactions regulating mandibular and maxillary arch patterning. Development 2000;127:403–12. Izadpanah R, Trygg C, Patel B, et al. Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. J Cell Biochem 2006;99:1285–97. Kern S, Eichler H, Stoeve J, Kluter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006;24:1294–301.
Available online at www.sciencedirect.com
http://intl.elsevierhealth.com/journals/mehy
Odontogenic differentiation of adipose-derived stem cells for tooth regeneration: necessity, possibility, and strategy Wei Jing, Ling Wu, Yunfeng Lin, Lei Liu, Wei Tang, Weidong Tian
*
Department of Oral and Maxillofacial Surgery, West China College of Stomatology, Sichuan University, No. 14, 3rd Sec., Ren Min Nan Road, Sichuan Province, Chengdu 610041, China Received 11 June 2007; accepted 11 July 2007
Summary Tooth regeneration using tissue engineering concepts is a promising biological approach to solving problems of tooth loss in elderly patients. The seeding cells, however, for tooth regeneration such as odontoblasts from dental germ, stem cells from dental pulp and deciduous teeth, and ectomesenchymal cells from the first branchial arch are difficult, even impossible to harvest in clinic. Bone marrow mesenchymal stem cells have odontogenic capacity, but their differentiation abilities significantly decrease with the increasing age of the donors. Therefore, the cells mentioned above are not practical in the clinical application of tooth regeneration in the old. Adipose derived stem cells have many clinical advantages over bone marrow mesenchymal stem cells, and their differentiation potential can be maintained with aging. Here we propose the hypothesis that adipose derived stem cells could be induced into odontogenic lineage and might be used as suitable seeding cells for tooth regeneration to replace the lost tooth of elderly patients. c 2007 Elsevier Ltd. All rights reserved.
Introduction and hypothesis Tooth loss due to decay or periodontal disease is a common occurrence in old people. Routine clinical treatments for tooth replacement, e.g., synthetic materials, may elicit an immune-induced host rejection response. Tooth regeneration using tissue engineering concepts is a promising biological approach that aims to regenerate natural tooth-like mineral tissues in terms of histology, morphology and function. Odontoblasts from dental germ, stem * Corresponding author. Tel.: +86 028 85503406. E-mail address: [email protected] (W. Tian).
cells from dental pulp and deciduous teeth, and ectomesenchymal cells from the first branchial arch showed odontogenic differentiation potential in basic research, whereas these cells are not practical to harvest in clinic [1–4]. Likewise, bone marrow mesenchymal stem cells (BMSCs) are not ideal seeding cells for old patients because these cells remarkably lose their differentiation ability with the donor age increasing [5]. In recent studies, adipose derived stem cells (ASCs) showed excellent pluripotency potential and many advantages over BMSCs [6–9], and their osteogenic potential can be maintained with aging [10,11]. Thus, ASCs are good alternatives for BMSCs used in hard tissue
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.07.010
Odontogenic differentiation of adipose-derived stem cells for tooth regeneration engineering. Therefore, we hypothesize that ASCs might probably have the ability to be induced into odontogenic lineage and could be a suitable source of cells for tooth regeneration especially in elderly patients.
Evaluation of the hypothesis Necessity of tooth regeneration using ASCs A key challenge in tooth regeneration is to find appropriate seeding cells that can be used in the clinic. The odontoblasts, as essential precursors during tooth development, appear to be an ideal source of seeding cells in tooth regeneration. Unfortunately, odontoblasts are mitotically mature and hard to separate and culture in vitro, which hinder their use for clinical purpose [1]. Stem cells derived from postnatal dental pulp and exfoliated deciduous teeth have been used for seeding [2,3], and the first branchial arch derived ectomesenchymal cells were proved able to differentiate into odontoblast-like cells in our previous study [4]. Whereas, obtaining these cells in the clinic is difficult, maybe even impossible. The multi-differentiation potential especially the osteogenic ability of adult stem cells such as BMSCs and ASCs has attracted increasing attention in hard tissue regenerative medicine. Recently, BMSCs were employed in tooth regeneration studies by different groups including ours, and showed capacities of odontogenic differentiation and tooth-like tissue formation [12–14]. It is well known, however, that the differentiation potential of BMSCs significantly decreases as donor age increases [5]. Moreover, the BMSCs used in the previous studies on tooth regeneration were from juvenile or young donors but not from old ones [12–14]. For these reasons, there is doubt that BMSCs are suitable for research and application of tooth regeneration in the elderly population. When contemplating clinical strategies, the ease of harvest, large number of cells and rapid in vitro expansion are attractive advantages of ASCs over BMSCs. Most important of all, it was shown both in vitro and in vivo that osteogenic potential of ASCs can be maintained with aging, which supports the potential of using ASCs as seeding cells for hard tissue engineering in an aging population [10,11].
The possibility that ASCs differentiate into odontogenic lineage Tooth develop from the sequential and reciprocal interactions between embryonic oral epithelial
541
cells and ectomesenchymal cells [15,16]. Many molecular and cellular studies have indicated that the fetal oral epithelium provides direct signals for the initiation and morphology confirmation during tooth development [17]. When these signals are received by ectomesenchymal cells, the biological process of odontogenesis is initiated [18]. In previous researches regarding tooth regeneration, odontogenesis could be induced by a combination of oral epithelium and BMSCs, demonstrating that nondental adult mesenchymal stem cells have sufficient plasticity to react with signals secreted by the oral epithelium [12,14]. ASCs, as a source of adult stem cells, not only have the potential to differentiate into cells of mesodermal origin, but have the ability to differentiate into cells of nonmesodermal origin, such as neurons, endocrine pancreatic cells, hepatocytes, endothelial cells, and cardiomyocytes [6,8]. Moreover, recent studies suggested that ASCs and BMSCs displayed similar expression profiles and multi-differentiation abilities [19,20]. Therefore, ASCs could probably have the capacity to be induced into odontogenic lineage in specific culture system.
Our strategy We have demonstrated both in vitro and in vivo that BMSCs can differentiate into functional odontoblast-like cells when co-cultured with embryonic oral epithelial cells and transplanted into the renal capsule of the SD rat [12]. This co-culture system and transplantation system can also be used in the experiments to test the hypothesis above. For in vitro test, its worth mentioned that ASCs should be labeled, for example, by the constructed adenovirus vector AD-GFP, before co-culture, so that they can be sorted by flow cytometry after co-culture and analyzed for their differentiation characteristics. For in vivo test, different types of cells should be centrifuged sequentially to ensure that the pellet of ASCs be overlayed with the embryonic oral epithelial cells to mimic the epithelium–mesenchyme interactions of tooth development in vivo.
Conclusion The replacement of lost teeth by whole tooth regeneration is one of the major goals of dental technology. ASCs have clinical advantages over other seeding cells that have been used in tooth regeneration research. If the hypothesis discussed here is true, ASCs will be a novel source of cells for tooth regeneration, and this will highlight the
542
Jing et al.
possibility of tooth replacement in elderly patients using tissue engineering approaches. [10]
References
[11]
[1] Linde A, Goldberg M. Dentinogenesis. Crit Rev Oral Biol Med 1993;4:679–728. [2] Gronthos S, Brahim J, Li W, et al. Stem cell properties of human dental pulp stem cells. J Dent Res 2002;81:531–5. [3] Miura M, Gronthos S, Zhao M, et al. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci USA 2003;100:5807–12. [4] Yan Z, Lin Y, Jiao X, et al. Characterization of ectomesenchymal cells isolated from the first branchial arch during multilineage differentiation. Cells Tissues Organs 2006;183:123–32. [5] Stenderup K, Justesen J, Clausen C, Kassem M. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone 2003;33:919–26. [6] Schaffler A, Buchler C. Concise review: adipose tissuederived stromal cells-basic and clinical implications for novel cell-based therapies. Stem Cells 2007;25:818–27. [7] Wu L, Wu Y, Lin Y, et al. Osteogenic differentiation of adipose derived stem cells promoted by overexpression of osterix. Mol Cell Biochem 2007;301:83–92. [8] Lin Y, Liu L, Li Z, et al. Pluripotency potential of human adipose-derived stem cells marked with exogenous green fluorescent protein. Mol Cell Biochem 2006;291:1–10. [9] Lin Y, Luo E, Chen X, et al. Molecular and cellular characterization during chondrogenic differentiation of
[12]
[13]
[14]
[15] [16]
[17] [18]
[19]
[20]
adipose tissue-derived stromal cells in vitro and cartilage formation in vivo. J Cell Mol Med 2005;9:929–39. Cowan CM, Shi YY, Aalami OO, et al. Adipose-derived adult stromal cells heal critical-size mouse calvarial defects. Nat Biotechnol 2004;22:560–7. Shi YY, Nacamuli RP, Salim A, Longaker MT. The osteogenic potential of adipose-derived mesenchymal cells is maintained with aging. Plast Reconstr Surg 2005;116:1686–96. Li ZY, Chen L, Liu L, Lin YF, Li SW, Tian WD. Odontogenic potential of bone marrow mesenchymal stem cells. J Oral Maxillofac Surg 2007;65:494–500. Hu B, Unda F, Bopp-Kuchler S, et al. Bone marrow cells can give rise to ameloblast-like cells. J Dent Res 2006;85: 416–21. Ohazama A, Modino SA, Miletich I, Sharpe PT. Stem-cellbased tissue engineering of murine teeth. J Dent Res 2004;83:518–22. Thesleff I. Epithelial-mesenchymal signalling regulating tooth morphogenesis. J Cell Sci 2003;116:1647–8. Jing W, Xuan M, Lin Y, et al. Odontogenic tumours: a retrospective study of 1642 cases in a Chinese population. Int J Oral Maxillofac Surg 2007;36:20–5. Thesleff I. Developmental biology and building a tooth. Quintessence Int 2003;34:613–20. Ferguson CA, Tucker AS, Sharpe PT. Temporospatial cell interactions regulating mandibular and maxillary arch patterning. Development 2000;127:403–12. Izadpanah R, Trygg C, Patel B, et al. Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. J Cell Biochem 2006;99:1285–97. Kern S, Eichler H, Stoeve J, Kluter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006;24:1294–301.
Available online at www.sciencedirect.com