Embryonic Stem Cells
A. Introduction
1. Ethics
The relation of embryonic stem cells (ESC) to human blastocysts promotes ethical, political, moral and emotional debate over their use in research. Thus, for the foreseeable future, the march of regenerative medicine to the clinic will depend upon the development of non-ESC therapy.
Jaing TH. Umbilical cord blood: a trustworthy source of mmultipotent stem cells for regenerative medicine. Cell Transplant 2014;23(4-5):493-6. on-line reference
2. Teratomas
In extensive experiments with embryonic stem cell induced pluripotent stem cells, the authors observed that both enzymatic passaging and feeder-free culture were associated with genetic instability, higher rats of cell proliferation and persistence of OCT4/POU5F1-positive cells in teratomas, with enzymatic passaging having the stronger effect. The authors also observed culture-associated variations in global gene expression and DNA methylation in both the embryonic and induced pluripotent stem cell cultures. The results highlight the need for careful assessment of the effects of culture conditions on cells intended for clinical therapies.
Garitaonandia I, Amir H, Boscolo FS, Wambua GK, Schultheisz HL, Sabatini K, Morey R, Waltz S, Wang YC, Tran H, Leonardo TR, Nazor K, Slavin I, Lynch C, Li Y, Coleman R, Gallego Romero I, Altun G, Reynolds D, Dalton S, Parast M, Loring JF, Laurent LC. Increased risk of genetic and epigenetic instability in human embryonic stem cells assocaited with specific culture conditions. PLoS 2015;10(2):e0118307. on-line reference
b. CDK Inhibition
The authors investigated the effects of cyclin-dependent kinases (CDKs) and found that they are associated with DNA damage response, nuclear stabilization, and anti-cell death factors in human and mouse embryonic stem cels (ESCs) but these factors were not found in differentiated cells. They also found that CDK1 inhibitors will inhibit ESC tumor formation and promote cell death in ESC-derived tumors. This research may be useful not only for embryonic and induced pluripotent stem cells but may also show benefit in other transformed stem cells as well.
Huskey NE, Guo T, Evason KJ, Momcilovic O, Pardo D, Creasman KJ, Judson RL, Blelloch R,Oakes SA, Hebrok M, Goga A. CDK1 inhibition targets the p53-NOXA-MCL1 axis, selectively killsembryonic stem cells, and prevents teratoma formation. Stem Cell Reports 2015;4(3):374-89. on-line reference
c. Filia and Genomic Stability
The authors discuss the benefits of Filia in mouse embryonic stem cells. Filia regulates genomic stability and genotoxic stress stimulates its expression. ESC genomic instability, caused by Filia's depletion, induces malignant transformation and resistance to cell death. Zhao B, Zhang WD, Duan YL, Lu YQ, Cun YX, Li CH, Guo K, Nie WH, Zhang R, Zheng P. Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genommic Stability. Cell Stem Cell 2015; Apr 29 [Epub ahead of print] on-line reference
3. Research in Developmental Biology
Embryonic stem cells (ESCs) have been shown to recapitulate normal developmental stages and can be useful in the study of developmental biology.
Shiraki N, Ogaki S, Kume S. Profiling of embryonic stem cell differentiation. Rev Diabet Stud 2014;11(1):102-14. on-line reference
4. Vitamin A and Stem Cells
Vitamin A is a key dietary component that plays a critical role in vertebrate development, cell differentiation, reproduction, vision and the immune system. New evidence has now emerged that retinol supports the self-renewal of stem cells including embryonic stem cells, germ line stem cells and cancer stem cells. This information can be used in cancer therapeutics.
Khillan JS. Vitamin A/retinol and maintenance of pluripotency of stem cells. Nutrients 2014;6(3):1209-22. on-line reference
5. Testing for Biomedical Applications
Embryonic stem cells (ESCs) represent one of the most powerful model system in basic research, drug discovery and biomedical applications. In the field of drug development, ESCs are instrumental in high-throughput/content screeening for the evaluation of compound libraries to test biological activity and toxic properties. The authors provide ESC protocols to screen molecules able to maintain self-renewal or to induce differentiation in ectodermal, mesodermal, endodermal cell lines and their derivatives.
Manganelli G, Masullo U, Filosa S. HTS/HCS to screen molecules able to maintain embryonic stem cell self-renewal or to induce differentiation: overview of protocols. Stem Cell Rev 2014;10(6):802-19. on-line reference
6. Embryonic Development and Heart Repair
Human heart formation is a complex event that depends on the correct temporal and spatial contribution of specific cell sources. During cardiac formation, cellular specification, differentiation, and rrearrangement are tightly regulated by an intricate signaling network. Several of these pathways have been shown to be functional or reactivated in cardiac disease. Knowledge from the study of heart development, embryonic stem cell differentiation adn cardiac pathophysiology can be helpful in developing new strategies for improved cardiac repair and regeneration.
Freire AG, Resende TP, Pinto-do-ÓP. Building and repairing the heart:what can we learn from embryonic development? Biomed Res Int 2014;2014:679168. on-line reference
B. Treatments
1. Neurogenesis for Learning and Memory
The author discusses the merits of transplanting human embryonic stem cell-derived neural progenitor cells into neuogenic niches of aged mice for facilitating adult neurogenesis. If generated new neurons are functionally integrated into the existing circuits of the aged hippocampus, synaptic plasticity in the hippocampus and learning/memory functions in aged mice should be enhanced.
Liu S, Li C, Xing Y, Tao F. Effect of transplantation of human embryonic stem cell-derived neural progenitor cells on adult neurogenesis in aged hippocampus. Am J Stem Cells 2014;3(1):21-6. on-line reference
2. Heart Failure
The authors produced embryonic stem cells committed to becoming cardiac progenitor cells. The cells were then surgically delivered to a patient (68 years old) with severe heart failure. The patient improved within three months, with no complications.
Menasché P, Vanneaux V, Hagège A, Bel A, Cholley B, Cacciapuoti I,Parouchev A, Benhamouda N, Tachdjian G, Tosca L, Trouvin JH, Fabreguettes JR, Bellamy V, Guillemain R, Suberbielle Boissel C,Tartour E, Desnos M, Larghero J. Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report. Eur Heart J 2015 May 19 [Epub ahead of print] on-line reference
3. Macular Degeneration
Four patients in Asia with macular degeneration were treated with human embryonic stem cells (hESC) derived retinal pigment epithelium and followed for twelve months. In three patients, visual acuity improved 9-19 letters and one patient remained stable. The treatment was safe. There were no complications and the authors propose that the process can be used for other patients with macular degeneration.
Song WK, Park KM, Kim HJ, Lee JH, Choi J, Chong SY, Shim SH,Del Priore LV, Lanza R. Treatment of macular degeneration using embryonic stem cell- derived retinal pigment epithelium: preliminary results in asian patients. Stem Cell Reports 2015,4(5):860-72. on-line reference
4. Spinal Cord Injury
The authors describe various drugs, growth factors, peptides and stem cell therapies that show improvements in spinal cord injury. Because there are a number of processes involved in spinal cord damage that need to be treated, the authors suggest a combined therapeutic approach for an effective treatment for this type of injury.
Siddiqui AM, Khazaei M, Fehlings MG. Translating mechanisms of neuroprotection, regeneration, and repair to treatment of spinal cord injury. Prog Brain Res 2015;218:15-54. on-line reference
