International Journal of Oral & Maxillofacial Pathology. 2012;3(2):37-42 Available online at http://www.journalgateway.com or www.ijomp.

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Review Article Stem Cells - Biological Solution to Biological Problems: A Review Anand Pratap Singh, Ankita Tandon, Sheetal Mujoo, Rajesh Mishra Abstract Hope is a prerequisite for any successful scientific innovation. Recent scientific discoveries in and molecular biology have been revolutionized and this new understanding of the biological processes will have great impact and change our lives in future. Stem cells have been successfully isolated from various human tissues including orofacial tissues. Research on stem cells continues to advance knowledge about how an organism develops from a single cell and how healthy cells replace damaged cells in adult organisms. Stem cell research is one of the most fascinating areas of contemporary biology, but, as with many expanding fields of scientific inquiry, research on stem cells raises scientific questions as rapidly as it generates new discoveries. Recent advances in stem cell biology and regenerative medicine have given opportunities for tissue engineering as well as gene based approaches in medical-dental therapies and are likely to revolutionize the entire health care delivery. Stem cells offer new potential to treat diseases, to screen new drugs in laboratory and to develop model systems to study normal growth and identify the causes of birth defects. Thus, by giving their unique regenerative abilities, stem cells offer new potential for treating diseases and has brought in a lot of optimistic hope amongst researchers, doctors, and the patients who are the chief beneficiary of this innovation. The present article reviews the various characteristics of stem cells & their applications in health care. Key words: Progenitor Cells;Regeneration;Adult;Embryonic Stem Cells;Totipotent; Pleuripotent; Multipotent;Biological Therapy;Biomedical Stem Cell Research.
Anand Pratap Singh, Ankita Tandon, Sheetal Mujoo, Rajesh Mishra. Stem Cells - Biological Solution to Biological Problems: A Review. International Journal of Oral and Maxillofacial Pathology; 2012:3(2):00-00. International Journal of Oral and Maxillofacial Pathology. Published by Publishing Division, Celesta Software Private Limited. All Rights Reserved. Received on: 13/03/2011 Accepted on: 19/05/2012

Introduction Cell is the basic unit of life. All human beings develop from the union of an egg and a sperm. The result is a fertilized egg, or zygote, a single cell that divides into other cells, which together constitute the early 1 embryo. The first few of the early embryonic 2 cells are totipotent. About two to eleven days after conception, a zygote divides into about 100 to 150 cells which form of a 1 hollow ball called a blastocyst , with a mass of undifferentiated cells inside it. These undifferentiated cells are used to generate embryonic stem cell lines. These embryonic stem cells are pluripotent and are capable of differentiating into all the types of cells that 3 comprise a human being. It has been observed that several tissues in the body (such as blood, skin, and gastrointestinal tract) undergo rapid renewal, and have regenerative ability. This observation led to hypothesize that the tissues with the regenerative potential may contain cells that initiate their replacement. These cells are termed as stem cells. The stem cells are uncommitted entities with a

capability of indefinite self-renewal to give rise to more stem cells and to differentiate into a number of specialized daughter cells 4,5 to perform specific function. Thus, stem cells are the pioneer of regenerative therapy. These cells were firstly suggested by Danchakoff and by Sabin and 6 Maximowmay. Stem cell technology is an upcoming field, but the regeneration of body part is not a new concept as the 7 regeneration of lizard tail (330 BC) and 8 bone marrow transplantation (1950s) has been previously reported. Recent revolutionization in cellular, molecular and developmental biology along with 7 replacement of chemistry by biotechnology has diverted our concentration towards biological solutions to biological problems, and an extraordinary ability of stem cell to self-renew and differentiating into one or 9 more specialized cell types and function , has introduced the stem cell therapy as a new optimistic hope in medicine and dentistry.

2012 International Journal of Oral and Maxillofacial Pathology. Published by Publishing Division, Celesta Software Private Limited. All Rights Reserved

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Properties Stem cells are unspecialized cells. Selfrenewal and differentiation potential are two 10 defining properties of stem cells. Selfregeneration is the ability of stem cells to 11 divide and produce more stem cells. During early development, the cell division is symmetrical and daughter cells have the same potential. Later in development, the cell divides asymmetrically and gives rise to one daughter stem cell and one progenitor 12 cell. The progenitor cell (derived from germ layer stem cells) is responsible to produce specialized cell with special function by 13 differentiation and is also called as Transitamplifying cells, Precursor cells, Lineage stem cells, and Tissue-determined stem cells. Progenitor cell undergoes asymmetrical, while a stem cell undergoes 14 symmetrical cell division. After the differentiation, most of the embryonic stem cells lose their ability to differentiate further and act as more specialized cells (process called determination). Only a small number of cells retain some ability to differentiate and called 15,16 as the adult stem cells. These multipotent cells replenish and repair many 17 cells of the body. Hierarchy sequence of stem cells during differentiation occurs as: zygote (totipotent), embryonal stem cells (pleuripotent), germ layer stem cell (multipotent), lineage stem cell or transitamplifying cells (oligopotent), tissuedetermined stem cell (tri or bi-potent) and 18 terminal cell (nullipotent). Classification and Sources Stem Cells can be classified according to their origin, potential for differentiation (characteristics), different models of cellular differentiation and capacity for tissue repopulation in vivo in short, medium or long time regeneration. I. Based on Origin, they can be classified into four broad types: a) Stem Cells From Embryo Blastocyst (5 - 7 days) embryonic stem cells. Gonadal ridge (6 week) embryonic germ cells. b) Stem Cells From Fetus Abortus (Fetal tissues) fetal stem cells. c) Stem Cells From Infant Umbilical cord blood stem cells. Whartons Jelly Umbilical cord matrix stem cells.
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d) Stem Cells From the Adult Germline Spermatogonia and Oogonia. Somatic Hemopoietic (Bone marrow and Peripheral Blood), Mesenchymal (Bone marrow Stroma), Liver, Epidermal (skin, hair), Neuronal, Eye, Gut, Pancreas. II. Based on Differentiation Potential which ranges from totipotent to nullipotent cells: Totipotent: Generate all types of cells including germ cells. Pluripotent: Generate all types of cells except cells of the embryonic membrane. Oligopotent: Differentiate into five types of blood cells (monocytes, macrophages, eosinophils, neutrophils and erythrocytes). Multipotent: Differentiate into more than one mature cell (skeletal muscle, cardiac muscle, liver cells, all blood cells). Quadripotent: Differentiate into four types of cells (cartilage cells, fat cells, stromal cells and bone-forming cells). Tripotent: Differentiate into three types of cells (2 types of astrocytes and oligodendrocytes). Bipotent: Differentiate into two types of cells (b cells and macrophages). Unipotent: Differentiate into single type of cell (mast cells). Nullipotent: No cell division and are terminally differentiated like red blood cells. Self-renewal: Divide without differentiation and create everlasting supply. Plasticity: Mature cells have plasticity and can undergo differentiation. The trigger for plasticity is stress or tissue injury which up regulates the stem cells and releases chemo-attractants and growth factors.

a) b)

c)

d)

e)

f)

g) h) i)

j)

k)

III.

Based on Different Models of Cellular Differentiation a. Direct-Differentiating: A specific type of cell developed in a multistep unidirectional pathway. b. Trans-Differentiating: Direct conversion of one cell type to another different cell type. c. De-Differentiating: A unipotent stem cell becoming a multipotent. d. Cell Fusion: A stem cell fusing with a somatic cell resulting in another lineage.

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Potential Applications in Medicine Stem cells are being explored for a variety of chronic debilitating diseases that have so far escaped remedial measures from traditional allopathic approaches with a hope that cell therapy would repair, repopulate, replace, and rewire tissues and organs regenerating hope and kindling confidence in such therapies. In the medical science, stem cell research is directed towards: brain 8,22 23,24 24 damage , cancer , spinal cord injury , 25,26 27 heart damage , haematopoiesis , 24 8 baldness , deafness , blindness and vision 12 24,28,29 impairment , parkinsons disease , 24 alzheimers disease , amyotrophic lateral sclerosis, multiple sclerosis, muscle 30 30 damage, diabetes , diabetic foot ulcer , 29 diabetic neuropathy , diseases such as severe combined immunodeficiency 30 disease , wiskott-aldrich syndrome, bone 31,32,33 diseases the autoimmune disease lupus, as well as AIDS and a number of 34 other impairments and conditions. Potential Applications in Dentistry The regenerative potential of adult stem cells obtained from various sources including dental tissues has been of interest for clinicians over the past years. The property of stem cells to reach the site of injury or disease makes them suitable in cell based therapy. The two common methods of cell delivery are intravenous injection and 36 cell encapsulation systems. In the field of dentistry, stem cell research is directed towards achieving the following: Regeneration of damaged coronal dentine 36 37 and pulp, regeneration of resorbed root , 36,37 cervical or apical dentin and perforations , 38 periodontal regeneration , craniofacial 39 defects by osteogenesis , whole tooth 40,41 regeneration (Figure 1) and treatment of 37 oral mucosal lesions (oral submucous fibrosis, oral lichen planus, dyskeratosis congenita, premalignant lesions like leukoplakia, recurrent oral ulcers, graft versus host disease and oral cancers). Advances in the isolation and understanding of dental stem cells have opened areas of research into the possibility to regrow lost dental tissues. This may not only prevent tooth loss but also fundamentally change the concept and definition of a dental caregiver. The impact of this source of stem cells is even more far-reaching for the medical field. Current research is exploring the capability of the dental stem cells to differentiate into non-dental tissues such as cardiac muscle. Previously untreatable patients may now be

improved by using stem cells harvested from 42 their own teeth.

Figure 1: Development of bioengineered tooth. Mesenchymal-originated dental stem cells possess a high self-renewal capacity and the potential to differentiate into mesodermal lineages thus forming cartilage, bone, adipose tissue, skeletal muscle, and the stroma of connective tissues. Mesenchymal progenitors have been assessed for tooth engineering purposes, such as progenitors 43 derived from teeth and bone marrow. Stem cells from human exfoliated deciduous 44 45 teeth , Dental pulp stem cells , Stem cells 46 from the apical part of the papilla , Dental 47 follicle stem cells , Periodontal ligament 48 stem cells , Bone marrow-derived 49 mesenchymal stem cells are examples of mesenchymal-originated dental stem cells. The major problem with epitheliumoriginated dental stem cells is that dental epithelial cells such as ameloblast and its precursors are eliminated soon after tooth eruption. Therefore, epithelial cells that could be stimulated in vivo to form enamel 43 are not present in the human adult teeth. Stem Cell Banking Cord stem cell preservation consists of collecting the 'leftover' umbilical cord blood from the placenta and umbilical cord after 50 the baby is delivered and the cord is cut. This blood is sent to a bank where it is processed and preserved by freezing them o in liquid nitrogen at temperature of -195 C. Many clinical studies showed that unrelated cord blood transplantation is safe and is an acceptable alternative to bone marrow transplantation for many patients. However, the studies also found that, as with bone marrow transplants, patients who receive

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cord blood from siblings or related donors generally have higher survival rates than those who receive cord blood from unrelated donors. Collecting and preserving a baby's cord blood stem cells would be a security blanket for the baby and his family members. In fact, it is estimated that the probability of a need for cord blood stem cells arising within a family is as high as 51 1/1,500. Challenges in Stem Cell Therapy For any new therapy to be accepted, it should either be more effective than or as effective as the existing therapy with added advantages in terms of technique being simpler, more predictable, long-lasting, time and cost-effective. If the above goal has to be achieved and if laboratory research has to be translated into clinical practice, there are certain barriers that have to be first understood and later overcome. Stem cells need to be differentiated to the appropriate cell types before they can be used clinically. Abnormalities in chromosome number and structure, possibility of rejection of stem cell 52 transplants as foreign tissue is very high. Conclusion The discovery of stem cells have proved to be a milestone in the health science and the possibility of stem cells for their use in the treatment of diverse degenerative diseases gives us a glimpse of their extraordinary prospects. A team effort engaging the expertise of the molecular biologists, immunologists, biomaterial scientists, cell biologists, matrix biologists, and practicing dental surgeons is crucial in attaining the desired goal. Even though technical problems are gradually being solved, the status of stem cells is being reviewed and although great progress is being made in the different fields as odontogenesis, neurogenesis or therapeutic clonation regarding the future of stem cells, there are still many aspects that need to be clarified. Thus, stem cells may be introduced as a biological solution to a biological problem and an alternative or adjuvant regenerative therapy in medicine and dentistry.
Author Affiliations 1. Dr.Anand Pratap Singh, Senior Lecturer, Department of Oral Medicine and Radiology, Rungta College of Dental Sciences and Research, Bhilai, Chhattisgarh, 2. Dr.Ankita Tandon, Senior Resident, Department of Oral Pathology, CSMMU, Lucknow, Uttar Pradesh, 3. Dr.Sheetal Mujoo, Junior Resident, 4.Dr.Rajesh Mishra, Resident, Department of Oral Medicine

and Radiology, Rungta College of Dental Sciences and Research, Bhilai, Chhattisgarh, India. Acknowledgement We would like to thank the staff members of the Oral Medicine and Oral Pathology department for their support & cooperation.

References 1. Singh IB, Pal GP. Textbook of Human embryology. 8th edition. Delhi: McMillan India Ltd; 2007. 2. Mitalipov S, Wolf D. Totipotency, pluripotency and nuclear reprogramming. Adv Biochem Eng Biotechnol 2009; 114:18599. 3. Bongso A, Richards M. History and perspective of stem cell research. In Best Practice and Research Clinical Obstetrics and Gynecology, eds. N. Fisk & J. Itskovitz, London: Elsevier Ltd; 2004. 4. Gronthos S, Akintoye SO, Wang CY, Shi S. Bone marrow stromal stem cells for tissue engineering. Periodontol 2000 2006; 41:188-95. 5. Smith A. A glossary for stem-cell biology. Nature 2006; 441:1060. 6. Alvarez A, Unda F, Canavate ML, Hilario E. Stem Cell and Regenerative Medicine. Curr Stem Cell Res Ther 2009; 4:287-97. 7. Nadig RR. Stem cell therapy Hype or Hope? A Review. J Conserv Dent 2009; 12(4):131-8. 8. Samadi F, Jaiswal JN, Gupta S. Stem cell therapy- Fascinating the World of Dentistry. UPSDJ 2008; 26(4):84-8. 9. Tsai RYL. A molecular view of stem cell and cancer cell self-renewal. Intl J Biochem Cell Biol 2004; 36:684-94. 10. Nerem R, Sambanis A. Tissue engineering-from biology to biological substitutes. Tissue Engineering 1995;1:3-13. 11. Keller GM. In vitro differentiation of embryonic stem cells. Curr Opin Cell Biol 1995; 7:862-9. 12. Fong HK, Foster BL, Popowics TE, Somerman MJ. The crowning Achievement: Getting to the root of the problem. J Dent Educ 2005;69(5):55570. 13. Beattie GM, Otonkoski T, Lopez AD. Functional beta-cell mass after transplantation of human fetal pancreatic cells: Differentiation or proliferation? Diabetes 1997;46:244-8. 14. Beckmann J, Scheitza S, Wernet P, Fischer JC, Giebel B. Asymmetric cell

ISSN 2231 2250

Stem Cells - Biological Solution to Biological Problems..... 41

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

division within the human hematopoietic stem and progenitor cell compartment: identification of asymmetrically segregating proteins. Blood 2007;109(12):5494501. Forbes SJ, Vig P, Poulsom R, Wright NA, Alison MR. Adult Stem Cell Plasticity: New Pathways of Tissue Regeneration become Visible. Clin Sci 2002;103:355-69. Poulsom R, Alison MR, Forbes SJ, Wright NA. Adult stem cell plasticity. J Pathol 2002;197:44156. Seo B, Miura M, Gronthos S, Bartold PM, Batouli S, Brahim J, et al. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 2004;364:14955. Daley GQ, Scadden DT. Prospects for stem cell-based therapy. Cell 2008;132:544-8. Fortier LA. Stem cells, classification, controversies and clinical applications. Vet Surg 2005;34:41523. Anderson DJ, Gage FH, Weissman IL. Can stem cells cross lineage boundaries? Nature 2001;7:393-5. Shamblott MJ, Axelman J, Wang S. Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc Natl Acad Sci USA 1998;95:1372631. Stiver SI, Tan X, Brown LF, HedleyWhyte ET, Dvorak HF. VEGF-A angiogenesis induces a stable neovascular in adult murine brain. J Neuropathol Exp Neurol 2004; 63:841 55. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells-cancer and cancer stem cells. Nature 2001;414(6859):105-111. Goldberg M, Smith AJ. Cells and extracellular matrices of dentin and pulp: a biological basis for repair and tissue engineering. Crit Rev Oral Biol Med 2004;15(1):13-27. Tateishi K, Takehara N, Matsubara H, Oh H. Stemming heart failure with cardiac- or reprogrammed-stem cells: Stem cells review series. J Cell Mole Med 2008;12:221732. Steinhauser ML, Lee RT. Cardiovascular regeneration: Pushing and pulling on progenitotors. Cell Stem Cell 2009;4:277-8. Le Blanc K, Ringden O. Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

transplantation. Biol Blood Marrow Transplant 2005;11:32134. Langston WJ. The promise of stem cells in Parkinson disease. Clin Invest 2005;115:23-5. Barker RA, Jain M, Armstrong RJ, Caldwell MA. Stem cells and neurological disease. J Neurol Neurosurg Psychiatry 2003;74:5537. Street CN, Sipione S, Helms L, Binette T, Rajotte RV, Bleackley RC, et al. Stem Cell-based Approaches to Solving the Problem of Tissue Supply for Islet Transplantation in Type I Diabetes. Int J Biochem Cell Biol 2004;36:667-83. Elisseef J, Puleo C, Yang F, Sharma B. Advances in skeletal tissue engineering with hydrogels. Ortho Craniofac Res 2005;8:15061. Shi S, Gronthos, Chen S, Reddi A, Counter CM, Robey PG, et al. Bone formation by human postnatal bone marrow stromal stem cells is enhanced by telomerase expression. Nat Biotechnol 2002;20:58791. Yamada Y, Ueda M, Naiki T, Nagasaka T. Tissue-engineered injectable bone regeneration for osseo implalnts. Clin Oral Implant Res 2004;15:58497. Goldman S, Windrem M. Cell replacement therapy in neurological disease. Philos Trans R Soc Lond B Biol Sci 2006;361(1473):146375. Hasegawa M, Yamato M, Kikuchi A, Okano T, Ishikawa I. Human periodontal ligament stem cell sheets can regenerate periodontal ligament tissue in athymical rat model. Tissue Eng 2005;11:469-77. Batouli S, Miura M, Brahim J, Tsutsui TW, Fisher LW, Gronthos S, et al. Comparison of stem cell mediated osteogenesis and dentinogenesis. J Dent Res 2003;82:976-81. Misra S, Singh N, Sharma A. STEM CELLS: Dentofacial RegenerationNewer Possibilities. J Oral Sign 2010;3(3):78-82. Ni-hung Lin, Gronthos S, Bartold PM. Stem cells and future periodontal regeneration. Periodontol 2000. 2009;51:23951. Hutmacher DW, Sittinger M, Risbud MV. Scaffold based tissue engineering: Rationale for compute solid free form fabrication systems. Trends Biotechnol 2004;22:354-62. Bluteau G, Luder HU, De Bari C, Mitsiadis TA. Stem cells for tooth

42

Anand Pratap Singh et al.,

ISSN 2231 - 2250

41.

42.

43.

44.

45.

46.

47.

engineering. European Cells Mater 2008;16:1-9. Miura M, Gronthos S, Zhao M, Lu B, Fischer LW, Robey PG, et al. SHED: Stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci USA. 2003;100:5807-54. Jamal M, Chogle S, Goodis H, Karam SM. Dental Stem Cells and Their Potential Role in Regenerative Medicine. J Med Sci 2011;4(2):53-61. Singh K, Mishra N, Kumar L, Agarwal KK, Agarwal B. Role of stem cells in tooth bioengineering. J Oral Biol Craniofac Res 2012;2(1):41-5. Miura M, Gronthos S, Zhao M, Bai Lu, Fisher LW, Robey PG, et al. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci USA 2003;100:580712. Mitsiadis TA, Rahiotis C. Parallels between tooth development and repair: conserved molecular mechanisms following carious and dental injury. J Dent Res 2004;83:896902. Sonoyama W, Liu Y, Fang D, Yamaza T, Seo BM, Zhang C, et al. Mesenchymal stem cell mediated functional tooth regeneration in swine. PLoS ONE 2006;1:79. Morsczeck C, Gotz W, Schierholz J, Zeilhofer F, Khn U, Mhl C, et al. Isolation of precursor cells (PCs) from

48.

49.

50.

51.

52.

human dental follicle of wisdom teeth. Matrix Biol 2005;24:15565. Gay I, Chen S, Mc dougall M. Isolation and characterization of multipotent human periodontal ligament stem cells. Ortho Craniofac Res 2007;10:14960. Kawaguchi H, Hirachi A, Hasegawa N, Takeda K, Mizuno N, Nishimura M, et al. Enhancement of periodontal tissue regeneration by transplantation of bone marrow mesenchymal stem cells. J Periodontol 2004;75:12817. Fuchs JR, Hannouche D, Terada S, Zand S, Vacanti JP, Fauza DO. Cartilage engineering from ovine umbilical cord blood mesenchymal progenitor cells. Stem Cells. 2005;23:95864. Alhadlaq A, Mao JJ. Mesenchymal stem cells: isolation and therapeutics. Stem Cells Dev 2004;13:436-48. Davis MW. Toward Development of an Implantable tissue engineered liver. Biomaterials 1996;17:336-72.

Corresponding Author Dr. Anand Pratap Singh, Department of Oral Medicine & Radiology, Rungta College of Dental Sciences and Research, Kohka-Kurud Road, Bhilai-Durg (India)-490023. Ph: +91-9425293935 E-mail: anandsingh001@gmail.com

Source of Support: Nil, Conflict of Interest: None Declared.