Atormac
Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 10215  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Search
 
  
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (360 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  

 
  In this Article
 »  Abstract
 »  Current Stem Cel...
 »  Therapeutic Pote...
 » Conclusions
 »  References

 Article Access Statistics
    Viewed5449    
    Printed206    
    Emailed1    
    PDF Downloaded150    
    Comments [Add]    
    Cited by others 10    

Recommend this journal

 


 
Table of Contents    
TOPIC OF THE ISSUE: REVIEW ARTICLE
Year : 2011  |  Volume : 59  |  Issue : 4  |  Page : 555-557

Induced pluripotent stem cells and promises of neuroregenerative medicine


1 University of Miami Miller School of Medicine, Miami, Florida, USA
2 Weill Cornell Medical College at Cornell University, New York, USA

Date of Submission09-Jul-2011
Date of Decision10-Jul-2011
Date of Acceptance10-Jul-2011
Date of Web Publication30-Aug-2011

Correspondence Address:
Ashok Verma
Clinical Research Building, 1120 NW 14 Street, Suite 1317, Miami, FL 33136
USA
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.84337

Rights and Permissions

 » Abstract 

First created in 2006 from adult somatic cells by a simple molecular genetic trick, induced pluripotent stem cells (iPS) system is the latest platform in stem cell research. Induced pluripotent stem cells are produced by nuclear reprogramming technology and they resemble embryonic stem cells (ES) in key elements; they possess the potentiality to differentiate into any type of cell in the body. More importantly, the iPS platform has distinct advantage over ES system in the sense that iPS-derived cells are autologous and therefore the iPS-derived transplantation does not require immunosuppressive therapy. In addition, iPS research obviates the political and ethical quandary associated with embryo destruction and ES research. This remarkable discovery of cellular plasticity has important medical implications. This brief review summarizes currently available stem cell platforms, with emphasis on cellular reprogramming and iPS technology and its application in disease modeling and cell replacement therapy in neurodegenerative diseases.


Keywords: Cell therapy, embryonic stem cell, induced stem cell, multipotent, pluripotent


How to cite this article:
Verma A, Verma N. Induced pluripotent stem cells and promises of neuroregenerative medicine. Neurol India 2011;59:555-7

How to cite this URL:
Verma A, Verma N. Induced pluripotent stem cells and promises of neuroregenerative medicine. Neurol India [serial online] 2011 [cited 2019 Nov 19];59:555-7. Available from: http://www.neurologyindia.com/text.asp?2011/59/4/555/84337


Neurodegenerative disorders represent a growing public health challenge. According to World Health Organization (WHO) estimates, [1] later age neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease make over 15% of the global burden of neurological illnesses, and the incidence of these disorders is expected to rise as life expectancy rises worldwide. Currently available therapy for neurodegenerative diseases is limited to partial relief of certain symptoms and the use of existing therapies often results in disabling side-effects. None of the currently available therapies slows or arrests the progressive clinical course of these disorders. The development of safe and efficacious preventive and curative therapies is urgently needed to reverse the tide of the emerging epidemiology of neurodegenerative disorders. It is in this context that stem cell research in recent years has caught public attention for novel restorative and replacement therapies in neurodegenerative disorders. This brief review summarizes the progress that has been made in stem cell research over the last few years, with an emphasis on the emergence of new induced pluripotent stem cells (iPS), the advantages of iPS over other stem cell platforms, and the role of iPS in understanding the disease mechanisms and devising potential cell therapies.


 » Current Stem Cell Platforms Top


Embryonic stem cells

A human embryo at the preimplantation stage (blastocyst, about 200-cell stage) is comprised of inner cell mass (ICM) and trophoblast. Cells of ICM are pluripotent and give rise to the embryo proper while trophoblast gives rise to the extraembryonic tissue required during gestation. A fertilized ovum on the other hand is totipotent as it can result in subsequent blastocyst and the whole fetus following successful implantation. Embryonic stem cells (ES) are derived from ICM and these cells have the potential to give rise to all tissues of the adult body through sequential differentiation of the ectoderm, endoderm, and mesoderm germ layers. All currently existing human ES lines are derived from the discarded fertilized ovum during in vitro fertilization (IVF) procedures. ES cells have been reported to develop into a comprehensive array of cell types under appropriate circumstances. However, meaningful therapeutic use of human ES has not yet been realized, despite reports of promising results in animal studies of neurological diseases [2] and Type 1 diabetes. [3]

Umbilical cord blood-derived stem cells

Umbilical cord blood (UBC)-derived progenitor cells comprise a heterogeneous pool of cells and it includes hematopoietic stem cells and embryonic-like stem cells. [4] These cells can be categorized as multipotent rather than pluripotent, as they are capable of giving rise to only hematopoietic and a limited spectrum of non-hematopoietic lineage cells. These cells have not been reported to possess the ability to give rise to the whole spectrum of adult body cells. However, storage of UBC samples has become a common commercialized venture worldwide as a result of long-term biobanking facilities.

Adult stem cells

Adult stem cells are tissue-resident progenitor cells, such as bone marrow-derived mesenchymal stem cells (MSC) and progenitor neurons in the periventricular and hippocampal regions of the brain. These cells are also multipotent in expression and they have been used in both site-directed and systemic deliveries of cells in a variety of disease models. Easy availability and multipotency of bone marrow-derived MSC have made them a common tool in tissue engineering experiments. [5]

Bioengineered stem cells

Bioengineered stem cells are derived using in vitro techniques to achieve multi- or pluripotency in adult differentiated cells. The bioengineering techniques that have been used to create pluripotency in committed adult cells can be classified into two general categories: somatic cell nuclear transfer (SCNT) technique and transcription factor-derived nuclear reprogramming or induced pluripotent stem cells (iPS) technology. SCNT is cloning as was demonstrated in 1997 through the creation of Dolly the sheep. [6] As the name SCNT suggests, it is simply the transfer of a somatic nucleus into an enucleated oocyte. This paradigm gives rise to a cloned zygote from which ES can subsequently be harvested. In contrast to the SCNT strategy in which an oocytic environment is required, iPS are derived by a novel technique in which nuclear reprogramming of ordinary adult cells is done by using a cocktail of transcription factors. [7] First reported in 2006, the iPS technology has been found to be remarkably reproducible and some say ridiculously easy [8] requiring only four factors (Oct4, Sox2, c-Myc, and Klf4). [7] As evidenced from the emerging literature from non-human iPS experiments, these cells meet the most stringent of tests for pluripotency (similar to EC), even up to autonomous capacity for embryogenesis. [9]

Thus, although multiple tools currently exist to generate human stem cells, only ES collected from discarded embryos during IVF procedures and iPS bioengineered from adult cells qualify for strict 'pluripotent' status. As the field of nuclear reprogramming technology is unfolding before us, early results indicate that iPS technology offers distinct biological and ethical advantages for its use in human diseases. First, reprogrammed somatic cells provide the opportunity for autologous cell transplant, thereby eliminating the need for immunosuppressive therapy. Second, tissue source (fibroblasts from skin biopsy, for example) for iPS is a whole lot easier and safer than IVF-derived embryo for ES. Third, iPS cells possess unlimited resource capacity from individual donors compared to the limited resource of ES from discarded IVF products. Finally, and most importantly, iPS technology avoids the often contentious ethical and political quandaries surrounding embryo destruction. As we look ahead, it may be reasonable to ask whether ES cells are necessary in the light of emerging iPS technology.


 » Therapeutic Potential of Induced Pluripotent Stem Cells Top


Aside from being an exciting research tool to probe embryogenesis and disease pathogenesis, iPS have potential for so-called 'disease modeling' for drug screening and custom-tailored cell therapy.

Induced pluripotent stem cells and disease modeling for drug development

The study of the disease mechanism in many neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, is constrained by the limited accessibility of the affected tissue as well as the inability to grow the relevant cell types in cultures for extended periods of time. The principle behind 'disease modeling' is to derive iPS from the patient's own skin cells and then to differentiate them in vitro into the affected cell types, thereby recapitulating the disease process in a ' Petri dish More Details'. One advantage of this paradigm is that the very cell type that is specifically compromised in disease can be recreated in culture and studied, even when the cell type is long lost in the patient. Further, iPS technology has the potential to provide an unlimited source for any desired specialized cells. Ultimately, the goal of this approach is to use these cell culture models of disease to screen and identify novel drugs to treat or prevent the disease. For example, iPS lines from patients suffering from spinal muscular atrophy [10] and familial dysautonomia [11] have been created that are providing novel data to understand the disease mechanisms. Remarkably, high-throughput preliminary screening for therapeutic small molecules has already begun in some neurodegenerative disorders.

Induced pluripotent stem cells and cell therapy

If autologous iPS are coaxed into the desired cell types, they can be transplanted as replacement tissue and it has obvious advantages over ES transplants. No immunosuppressive therapy is required following iPS transplantation because they are autologous in nature. Another key advantage of iPS is the possibility of repairing disease-causing mutations by homologous DNA recombination technology. Promising results in mice indeed suggest that the treatment of genetic disorders with iPS is feasible. [11]

Despite some successes in animal models, iPS technology is not yet ready for human trials. The chief concern is safety; [12] current iPS protocols cannot efficiently eliminate residual and unwanted undifferentiated cells and just like EC, they tend to be oncogenic and form teratomas. Additionally, most patient-specific iPS have been generated using integrating vectors, which may not get silenced efficiently or could disrupt endogenous genes, and is a potential impediment in human iPS therapy. [13] Other hurdles include lack of efficient targeting strategies to repair mutant alleles. Recent observation that many mouse iPS harbor epigenetic abnormalities, they may develop genetic mutation on prolonged culture and they may continue to retain epigenetic memory of their donor cells also need to be addressed. [13],[14]


 » Conclusions Top


Created from adult cells by a simple genetic trick just five years ago, the iPS system seems to resemble the ES platform that might allow them to become any type of cell in the body. The iPS concept is so appealing that some scientists and policy-makers even argue that other approaches such as therapeutic cloning and ES research, which requires destruction of embryos, is unnecessary and should be halted. While many questions remain and more questions are bound to come up as iPS technology is applied in disease modeling and cell therapy programs, interesting insights have already been gained into the process of cell programming, such as the finding that cells undergo defined sequential molecular events that are influenced by the starting cell type as well as the choice and number of transcription factors. It remains to be tested, however, whether iPS reprogramming and differentiation works in the human system, and whether lineage converted cells are functionally equivalent to their in vivo counterparts.

 
 » References Top

1.World Health Organization. Neurological disorders: Public health challenges. Geneva: WHO press; 2006.  Back to cited text no. 1
    
2.Goldman S. Stem and progenitor cell-based therapy of the human central nervous system. Nat Biotechnol 2005;23:862-71.  Back to cited text no. 2
[PUBMED]  [FULLTEXT]  
3.Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 2008;26:443-52.  Back to cited text no. 3
[PUBMED]  [FULLTEXT]  
4.McGuckin C, Jurga M, Ali H, Strbad M, Forraz N. Culture of embryonic-like stem cells from human umbilical cord blood and onward differentiation to neural cells in vitro. Nat Protoc 2008;3:1046-55.  Back to cited text no. 4
[PUBMED]  [FULLTEXT]  
5.Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: Mesenchymal stem cells: Their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 2007;25:2739-49.  Back to cited text no. 5
[PUBMED]  [FULLTEXT]  
6.Wilmut I, Schneike AE, McWhir J, King AJ, Campbell KH. Viable offspring derived from fetal and adult mammalian cells. Nature 1997;385:810-13.  Back to cited text no. 6
    
7.Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663-76.  Back to cited text no. 7
[PUBMED]  [FULLTEXT]  
8.Cyranoski D. Stem cells: 5 things to know before jumping on the iPS bandwagon. Nature 2008;452:406-8.  Back to cited text no. 8
[PUBMED]  [FULLTEXT]  
9.Zhao XY, Li W, Lv Z, Liu L, Tong M, Hai T, et al. Viable fertile mice generated from fully pluripotent iPS cells derived from adult somatic cells. Stem Cell Rev 2010;6:390-7.  Back to cited text no. 9
[PUBMED]  [FULLTEXT]  
10.Ebert AD, Yu J, Rose FF Jr, Mattis VB, Lorson CL, Thomson JA, et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 2009;457:277-80.  Back to cited text no. 10
[PUBMED]  [FULLTEXT]  
11.Lee G, Papapetrou EP, Kim H, Chambers SM, Tomishima MJ, Fasano CA, et al. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 2009;461:402-6.  Back to cited text no. 11
[PUBMED]  [FULLTEXT]  
12.Xu D, Alipio Z, Fink LM, Adcock DM, Yang J, Ward DC, et al. Phenotypic correction of murine hemophilia A using an iPS cell-based therapy. Proc Natl Acad Sci USA 2009;106:808-13.  Back to cited text no. 12
[PUBMED]  [FULLTEXT]  
13.Stadtfeld M, Hochedlinger K. Induced pluripotency: history, mechanisms, and applications. Genes Dev 2010;24:2239-63.   Back to cited text no. 13
[PUBMED]  [FULLTEXT]  
14.Panopoulos AD, Ruiz S, Izpisua Belmonte JC. iPSCs: Induced back to controversy. Cell Stem Cell 2011;8:347-8.  Back to cited text no. 14
[PUBMED]  [FULLTEXT]  



This article has been cited by
1 Induced Pluripotent Stem Cell-Derived Neural Stem Cell Transplantations Reduced Behavioral Deficits and Ameliorated Neuropathological Changes in YAC128 Mouse Model of Huntingtonæs Disease
Abeer Al-Gharaibeh,Rebecca Culver,Andrew N. Stewart,Bhairavi Srinageshwar,Kristin Spelde,Laura Frollo,Nivya Kolli,Darren Story,Leela Paladugu,Sarah Anwar,Andrew Crane,Robert Wyse,Panchanan Maiti,Gary L. Dunbar,Julien Rossignol
Frontiers in Neuroscience. 2017; 11
[Pubmed] | [DOI]
2 Cellular reprogramming for clinical cartilage repair
Britta J.H. Driessen,Colin Logie,Lucienne A. Vonk
Cell Biology and Toxicology. 2017; 33(4): 329
[Pubmed] | [DOI]
3 Current Concept of Stem Cell Therapy for Spinal Cord Injury: A Review
Sun Kyu Oh,Sang Ryong Jeon
Korean Journal of Neurotrauma. 2016; 12(2): 40
[Pubmed] | [DOI]
4 The epigenetics of aging and neurodegeneration
Roy Lardenoije,Artemis Iatrou,Gunter Kenis,Konstantinos Kompotis,Harry W.M. Steinbusch,Diego Mastroeni,Paul Coleman,Cynthia A. Lemere,Patrick R. Hof,Daniel L.A. van den Hove,Bart P.F. Rutten
Progress in Neurobiology. 2015; 131: 21
[Pubmed] | [DOI]
5 Alzheimeræs disease modeling: Ups, downs, and perspectives for human induced pluripotent stem cells
Wojda, U. and Kuznicki, J.
Journal of Alzheimeræs Disease. 2013; 34(3): 563-588
[Pubmed]
6 Stem cell therapy for the spinal cord
Donnelly, E.M. and Lamanna, J. and Boulis, N.M.
Stem Cell Research and Therapy. 2012; 3(4)
[Pubmed]
7 Functionalized Nanostructures with Application in Regenerative Medicine
Macarena Perán,María A. García,Elena López-Ruiz,Milán Bustamante,Gema Jiménez,Roberto Madeddu,Juan A. Marchal
International Journal of Molecular Sciences. 2012; 13(12): 3847
[Pubmed] | [DOI]
8 Functionalized nanostructures with application in regenerative medicine
Perán, M., García, M.A., López-Ruiz, E., Bustamante, M., Jiménez, G., Madeddu, R., Marchal, J.A.
# # International Journal of Molecular Sciences. 2012; 13(3): 3847-3886
[Pubmed]
9 Stem cell therapy for the spinal cord
Eleanor M Donnelly,Jason Lamanna,Nicholas M Boulis
Stem Cell Research & Therapy. 2012; 3(4): 24
[Pubmed] | [DOI]
10 Induced pluripotent stem cells
Manal Hassan Moussa
The Egyptian Journal of Histology. 2011; 34(4): 621
[Pubmed] | [DOI]



 

Top
Print this article  Email this article
   
Online since 20th March '04
Published by Wolters Kluwer - Medknow