Embryonic stem cells induced pluripotent stem cells deconstructing stem cell tumorigenicity. Here, we developed a new protocol for the efficient differentiation of human induced pluripotent stem cells hipscs into nplike cells in vitro. Human embryonic stem cells and induced pluripotent stem cells. Induced pluripotent stem cells in alzheimers disease. This differentiation strategy derives from our knowledge of the embryonic notochordal lineage of np cells as well as strategies used to support healthy np cell phenotypes for primary cells in vitro. Induced pluripotent stem cells are similar to natural pluripotent stem cells, such as embryonic stem es cells, in many aspects, such as the expression of certain stem cell genes and proteins, chromatin methylation patterns, doubling time, embryoid body formation, teratoma formation, viable chimera formation, and potency and differentiability. Therefore, human pscs hold great promise for regenerative medicine.
Since the discovery of induced pluripotent stem cells ipscs, which have similar properties to hescs but less ethical issues than hescs, can be created directly. Then, in 1998, the first human embryonic stem cells hescs were isolated by james thomson in the usa 3. Tumorigenicity as a clinical hurdle for pluripotent stem. An insight into dnafree reprogramming approaches to generate. Human embryonic stem cells hescs are the in vitro descendants of the pluripotent inner cell mass icm of human blastocyst stage embryos. Often this is referred to as a pluripotency assay, but of course it is also a tumor assay. Electrophysiological properties of human induced pluripotent stem cells peng jiang,1,2 stephanie n. Dissecting the oncogenic and tumorigenic potential of. Tumorigenicity testing is therefore a key preclinical safety test in pscderived cell therapy. However, the fundamental question is still under debate whether stem cell based disease modeling and drug discovery are applicable for recapitulating pathological processes under in vivo conditions. Differential methylation of tissue and cancerspecific cpg island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts.
It was assumed that human induced pluripotent stem cells hipscs would behave like their embryonic counterparts in respect to their tumorigenicity, but a rapidly accumulating body of evidence. Tumorigenicity studies for human pluripotent stem cell. The trials have used human embryonic stem cell hescderived retinal pigment epithelium rpe 14. Hence, the tumorigenicity of human embryonic stem cells hescs has been extensively studied.
Until recently, it was assumed that human induced pluripotent stem cells hipscs would behave like their embryonic counterparts in respect to their tumorigenicity. Embryonic and induced pluripotent stem cells markers. Brivanlou laboratory of molecular embryology, the rockefeller university, new york, new york, usa. The tumorigenicity of human embryonic and induced pluripotent stem cells. Frontiers induced pluripotent stem cellbased cancer. Neural stem progenitor cell nspc transplantation derived from fetal tissues or embryonic stem cells escs has demonstrated therapeutic effects via replacement of lost neurons and severed axons and creation of permissive microenvironment to promote repair of spinal cord and axon. Aneuploidy induces profound changes in gene expression. Pdf human embryonic and induced pluripotent stem cells in. Defining essential genes for human pluripotent stem cells by crisprcas9 screening in haploid cells. Bendavid u, benvenisty nthe tumorigenicity of human embryonic and induced pluripotent stem cells. Human pluripotent stem cells hpscs can be expanded indefinitely and differentiate into any cell type in the body. Hipscs from somatic human cells was reported the following year.
The promise of induced pluripotent stem cells ipscs. It was assumed that human induced pluripotent stem cells hipscs would behave like their embryonic counterparts in respect to their tumorigenicity, but a. Human pluripotent stem cells hpscs tend to acquire genomic aberrations in culture, the most common of which is trisomy of chromosome 12. Pluripotent stem cells pscs, including embryonic escs and induced pluripotent stem cells ipscs, offer immense potential as a source for regenerative therapies, as was recently recognized by the 2012 nobel committee in medicine. In 2007, okita and colleagues generated induced pluripotent cell lines from mouse embryonic. Because of these abilities, numerous attempts have been made to utilize hpscs in regenerative medicinecell therapy. An insight into dnafree reprogramming approaches to. The tumorigenic potential of pluripotent stem cells. Embryonic stem cellsinduced pluripotent stem cells deconstructing stem cell tumorigenicity. Hscs can be generated from induced pluripotent stem cells ipscs, which requires the understanding of the. Nov 11, 2018 more than a decade ago, a pioneering study reported generation of induced pluripotent stem cells ipscs by ectopic expression of a cocktail of reprogramming factors in fibroblasts. Pluripotent stem cells, both human embryonic stem cells hesc and human induced pluripotent stem cells hipsc, can give rise to multiple cell types and hence have tremendous potential for regenerative therapies.
Current perspective on evaluation of tumorigenicity of. Applications for the use of induced pluripotent stem cells and related concerns. However, the tumorigenic potential of these cells remains a great concern, as reflected in the formation of teratomas by transplanted pluripotent cells. However, questions remain regarding the tumorigenic potential of such cells. Current perspective on evaluation of tumorigenicity of cellular and tissuebased products derived from induced pluripotent stem cells ipscs and ipscs as their starting materials. Mouse clone model for evaluating the immunogenicity and. This report shed shadows on the great promise of ipscs as the renewable sources of autologous cells for regenerative medicine. Embryonic stem cells escs and induced pluripotent stem cells ipscs have the ability i to duplicate indefinitely while maintaining pluripotency and ii to differentiate into cell types of all three embryonic germ layers. The initial results from multiple clinical trials demonstrate that hescbased therapies are safe and promising. Here, we report the tumorigenic potential of induced pluripotent stem cell ipscderived retinal pigment epithelium rpe for the treatment of wettype, agerelated macular.
In particular, the medical applications of human ipscs in disease modeling and stem cell therapy have been. Here we dissect the cellular and molecular implications. The tumorigenicity of human embryonic and induced pluripotent. However, the ability of undifferentiated hescs to produce tumors in vivo presents a major obstacle for the translation of this potential into clinical reality. A schematic illustration of the generation and application of an autologous ipscbased cancer vaccine in patients. Steps toward safe cell therapy using induced pluripotent. Tumorigenicity testing becomes particularly important when autologous human induced pluripotent stem cell ipscderived cell products with no immunobarrier are considered for transplantation.
Induced pluripotent stem cells can divide indefinitely and are able to differentiate into every cell type, which make them viable for transplantation and individual disease modeling. Efficient generation of transgenefree human induced pluripotent stem cells ipscs by temperaturesensitive sendai virus vectors. It is remarkable that, to date, one of the most common assays for demonstrating and studying the pluripotency of stem cells, including induced pluripotent stem cells ipsc, is the teratoma assay. The recently developed and optimized induced pluripotent stem cells ipscs technology may provide an appealing access to overcome these challenges in ad research. Stem cells hold great promise for regenerative medicine as they have the potential to repair almost any tissue. Efficient, selective removal of human pluripotent stem cells. Induced pluripotent stem cells ipscs and embryonic stem cells escs are two types of pluripotent stem cells that hold great promise for biomedical research and medical applications. These two key features make hpscs an ideal source of transplantable cells for medical and research purposes, which has raised hope that they could fundamentally change the way that many diseases are treated.
Thus, cell therapy using human pluripotent stem cells hpscs has reached clinical. Tumorigenicity studies of induced pluripotent stem cell ipsc. Hematopoietic stem cells from induced pluripotent stem. Human induced pluripotent stem cells hipscs can be generated from patients somatic cells and in vitro derivation of functional germ cells from patientspecific ipscs may provide new therapeutic strategies for infertile couples. Human induced pluripotent stem cells and male infertility.
Neural stemprogenitor cell nspc transplantation derived from fetal tissues or embryonic stem cells escs has demonstrated therapeutic effects via replacement of lost neurons and severed axons and creation of permissive microenvironment to promote repair of spinal cord and axon. Genomescale dna methylation maps of pluripotent and differentiated cells. Tumorigenicity as a clinical hurdle for pluripotent stem cell. Spinal cord injury sci is an intractable and worldwide difficult medical challenge with limited treatments. Differentiation of human induced pluripotent stem cells into. Immunogenicity and tumorigenicity of human pluripotent stem. Isolate and culture pluripotent stem cells can be efficiently expanded in culture using specialized media and growth factors. More than a decade ago, a pioneering study reported generation of induced pluripotent stem cells ipscs by ectopic expression of a cocktail of reprogramming factors in fibroblasts. However, viral integration into the host genome increases the risk of tumorigenicity. Induced pluripotent stem cells in medicine and biology. Generation of mouse induced pluripotent stem cells without. The promise of induced pluripotent stem cells ipscs potentially more efficient integrative approaches. Induced pluripotent stem cells ipscs have immense potential to generate a variety of cell types for disease modeling, drug development, and cell therapy takahashi and yamanaka, 2006. Human induced pluripotent stem cells ipscs are a type of stem cells that can be derived from human somatic cells by introducing certain transcription factors.
Pluripotent stem cells, both human embryonic stem cells hesc and humaninduced pluripotent stem cells hipsc, can give rise to multiple cell types and hence have tremendous potential for regenerative therapies. Nevertheless, an issue that has slowed the use of ipsc as well as hesc in the clinic is safety. This study has revolutionized stem cell research and has garnered immense interest from the scientific community globally. Apr 21, 2020 the tumorigenicity of human embryonic and induced pluripotent stem cells until recently, it was assumed that human induced pluripotent stem cells hipscs would behave like their embryonic counterparts in respect to their tumorigenicity. Induced pluripotent stem cell lines derived from human. Differentiation of human induced pluripotent stem cells. Embryonic stem cells grown in mouse pluripotent stem cell media express pluripotency stem cell markers, ssea1 and oct34, and lack ssea4.
Genomewide screen for culture adaptation and tumorigenicity. The promise of human induced pluripotent stem cells for research and therapy. Design of a tumorigenicity test for induced pluripotent stem. For full access to this pdf, sign in to an existing account, or purchase an annual subscription.
Tatsutoshi nakahata, chair, cellular and tissue based products subcommittee. Because of the huge potential of human embryonic stem hes cells, especially the newly developed human induced pluripotent stem hips cells, in disease treatment and life quality improvement, enormous efforts have been made to develop new methodologies to translate lab discoveries in stem cell research into bedside clinical technologies. Thus human pluripotent stem cells hpscs have an important role in biomedical research and future regenerative medicine, especially with the ability to reprogram somatic cells into induced pluripotent stem cells bendavid et al. Human embryonic stem cells hescs and induced pluripotent stem cells hipscs offer an immense potential as a source of cells for regenerative medicine. Induced pluripotent stem cells ipscs for research and. Pdf bendavid u, benvenisty nthe tumorigenicity of human. The tumorigenicity of human embryonic stem cells sciencedirect. Hideyuki okano, vicechair, cellular and tissue based products subcommittee. Ever since pioneering reports introduced mouse 1 and humaninduced 2 4 pluripotent stem cells ipscs to the scientific community and the populace at large, there has been an increasing interest in applications for their use in the fields of biomedical research. Human pluripotent stem cells hpscs have the potential to. The trials have used human embryonic stem cell hescderived retinal pigment epithelium rpe. In particular, the medical applications of human ipscs in disease modeling and stem cell therapy have been progressing. Another viable alternative is to induce stem cells from autologous somatic cells.
Human embryonic stem cells hescs are pluripotent cells derived from the inner cell mass icm of a human blastocyst stage embryo thomson et al. These human induced pluripotent stem cells have normal karyotypes, express telomerase activity, express cell surface markers and genes that characterize human es cells, and maintain. The discovery of induced pluripotent stem cells ipscs has opened up unprecedented opportunities in the pharmaceutical industry, in the clinic and in laboratories. Embryonic stem es cells and induced pluripotent stem ips cells are selfrenewing progenitors that have the capacity to differentiate into cells of the ectoderm, mesoderm, and endoderm. Human embryonic stem cells hescs are the first characterized pluripotent stem cells that could be induced to generate all types of cells including retinal neurons, for example, retinal pigment epithelium rpe cells 1, 2. Proceedings of the national academy of sciences of the united states of america.
The overall developmental dynamics of human primordial germ cells are similar to that in mice, but accumulating. These factors were chosen because they were known to be involved in the maintenance. Human induced pluripotent stem cells hipscs are discussed as disease modeling for optimization and adaptation of therapy to each individual. Human embryonic and induced pluripotent stem cells. Rushing,1,2 chiwing kong,1,2,3,4 jidong fu,1,2 deborah kuoti lieu,1,2 camie w. Why are there concerns over the safety of ips cells. Sep 29, 2010 embryonic stem cells escs and induced pluripotent stem cells ipscs have the ability i to duplicate indefinitely while maintaining pluripotency and ii to differentiate into cell types of all three embryonic germ layers. Induced pluripotent stem ips cells have been generated from mouse and human somatic cells by introducing oct34 and sox2 with either klf4 and cmyc or nanog and lin28 using retroviruses or lentiviruses. Mar 10, 2011 it was assumed that human induced pluripotent stem cells hipscs would behave like their embryonic counterparts in respect to their tumorigenicity, but a rapidly accumulating body of evidence. The use of induced pluripotent stem cells ipsc offers several advantages over human embryonic stem cells hesc. Efficient, selective removal of human pluripotent stem.
To generate an autologous ipscbased cancer vaccine, peripheral blood mononuclear cells pbmcs are isolated from the patients blood and reprogrammed into induced pluripotent stem cells ipscs by the introduction of four yamanaka factors oct4, klf4, sox2, and cmyc. Thus, cell therapy using human pluripotent stem cells hpscs has reached clinical application. Although hematopoietic stem cell hsc therapy for hematological diseases can lead to a good outcome from the clinical point of view, the limited number of ideal donors, the comorbidity of patients and the increasing number of elderly patients may limit the application of this therapy. Patientspecific ips cells could be useful in drug discovery and regenerative medicine. Embryonic stem cells induced pluripotent stem cells smad7 directly converts human embryonic stem cells to telencephalic fate by a default mechanism mohammad zeeshan ozair,scott noggle,aryeh warmflash,joanna ela krzyspiak,ali h. Immunogenicity and tumorigenicity of human pluripotent. Tumorigenicity of induced pluripotent stem cellderived neural stemprogenitor cells junhao deng, yiling zhang, yong xie, licheng zhang, and peifu tang department of orthopaedics, chinese pla general hospital, no. In addition, several groups are planning clinical trials with autologous human induced pluripotent stem cell hipscderived rpe for the wet type of amd. Li1,2,3,4 1institute of pediatric regenerative medicine, shriners hospital for children of north america, sacramento. Pluripotent stem cells pscs, including human embryonic stem cells hescs and induced pluripotent stem cells ipscs, are capable of unlimited selfrenewal and differentiating into all types of cells. Tumorigenicity studies of induced pluripotent stem cell.
Tumorigenicity testing of mesenchymal stem cells may not reveal a serious problem 10. The tumorigenicity of human embryonic and induced pluripotent stem cells until recently, it was assumed that human induced pluripotent stem cells hipscs would behave like their embryonic counterparts in respect to their tumorigenicity. Hescs can be kept undifferentiated in culture or be differentiated to tissues representing all three germ layers, both in vivo and in vitro. The tumorigenicity of diploid and aneuploid human pluripotent. Therefore, characterizing the nature of hescderived tumors, especially. Tumorigenicity of induced pluripotent stem cellderived neural stem progenitor cells junhao deng, yiling zhang, yong xie, licheng zhang, and peifu tang department of orthopaedics, chinese pla general hospital, no. Induced pluripotent stem cells ipscs for research and therapy. However, in the case of pscderived cell products, the tumorforming potential should be examined thoroughly because of the unlimited proliferation capacity of psc and their genetic instability. Basic studies of human pluripotential stem cells have advanced rapidly and stem cell products are now seeing therapeutic applications. Design of a tumorigenicity test for induced pluripotent. Differentiated cells can be reprogrammed to pluripotency and other cell fates by treatment with defined factors. Embryonic stem cells or induced pluripotent stem cells. However, a rapidly accumulating body of evidence suggests that there are important genetic and epigenetic.
1521 1103 204 749 48 269 583 669 289 999 513 508 721 690 1277 544 251 366 734 312 617 1003 1390 371 252 288 765 454 144 462 781 730