Int J Stem Cells.  2018 Jun;11(1):105-110. 10.15283/ijsc17064.

Human Embryonic Stem Cell Derived from Early Stage Fertilized Ovum: Non Immunogenic and Universal, Neuronal and Non-neuronal Cell Lines

• Shroff G
• Srivastav
• Shroff R

• KMID: 2413506
• DOI: http://doi.org/10.15283/ijsc17064

Abstract

BACKGROUND
Human embryonic stem cells (hESCs) have the potential to treat various human disorders currently labeled as incurable and/or terminal illness. However, the fear that the patients' immune system would recognize them as non self and lead to an immune rejection has hampered their use. The main cause for immune rejection is usually the incompatibility of both donor and recipient's major histocompatibility complex (MHC).
METHODS
We describe a hESC line developed through a patented technology that does not lead to immune reaction upon transplantation. We have transplanted these cells in >1,400 patients with chronic/terminal conditions and did not observe any immune reaction. No immunosuppressant were administered to these patients. We analyzed the expression levels of MHC-I and MHC-II on the surface of these hESCs using microarray technology. The gene targets for miRNA were analyzed using Gene ontology and DAVID database and pathways for these genes were determined using Reactome and Panther databases.
RESULTS
Our results showed that the levels of expression of MHC-I and MHC-II on hESCs is almost negligible and thus the hESCs are less susceptible to an immune rejection.
CONCLUSIONS
The hESCs cultured at our facility expresses low levels of MHC-I and do not produce an immune reaction. These can be administered universally and need no cross matching before transplantation.

Keyword

Human embryonic stem cells; Major histocompatibility complex; DAVID; Microarray technology; Reactome; miRNA

MeSH Terms

Cell Line*
Gene Ontology
Human Embryonic Stem Cells*
Humans*
Immune System
Major Histocompatibility Complex
MicroRNAs
Neurons*
Tissue Donors
Zygote*
MicroRNAs

Reference

References

1. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998; 282:1145–1147. DOI: 10.1126/science.282.5391.1145. PMID: 9804556.

2. Batten P, Rosenthal NA, Yacoub MH. Immune response to stem cells and strategies to induce tolerance. Philos Trans R Soc Lond B Biol Sci. 2007; 362:1343–1356. DOI: 10.1098/rstb.2007.2120. PMID: 17584730. PMCID: 2440400.

3. Alper J. Geron gets green light for human trial of ES cell-derived product. Nat Biotechnol. 2009; 27:213–214. DOI: 10.1038/nbt0309-213a. PMID: 19270655.

4. Gage FH. Cell therapy. Nature. 1998; 392(6679 Suppl):18–24. PMID: 9579857.

5. Menendez P, Bueno C, Wang L, Bhatia M. Human embryonic stem cells: potential tool for achieving immunotolerance? Stem Cell Rev. 2005; 1:151–158. DOI: 10.1385/SCR:1:2:151.

6. Roopenian D, Choi EY, Brown A. The immunogenomics of minor histocompatibility antigens. Immunol Rev. 2002; 190:86–94. DOI: 10.1034/j.1600-065X.2002.19007.x. PMID: 12493008.

7. Swijnenburg RJ, Schrepfer S, Govaert JA, Cao F, Ransohoff K, Sheikh AY, Haddad M, Connolly AJ, Davis MM, Robbins RC, Wu JC. Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts. Proc Natl Acad Sci U S A. 2008; 105:12991–12996. DOI: 10.1073/pnas.0805802105. PMID: 18728188. PMCID: 2529073.

8. Fändrich F, Lin X, Chai GX, Schulze M, Ganten D, Bader M, Holle J, Huang DS, Parwaresch R, Zavazava N, Binas B. Preimplantation-stage stem cells induce long-term allogeneic graft acceptance without supplementary host conditioning. Nat Med. 2002; 8:171–178. DOI: 10.1038/nm0202-171. PMID: 11821902.

9. Drukker M, Katz G, Urbach A, Schuldiner M, Markel G, Itskovitz-Eldor J, Reubinoff B, Mandelboim O, Benvenisty N. Characterization of the expression of MHC proteins in human embryonic stem cells. Proc Natl Acad Sci U S A. 2002; 99:9864–9869. DOI: 10.1073/pnas.142298299. PMID: 12114532. PMCID: 125045.

10. Drukker M, Katchman H, Katz G, Even-Tov Friedman S, Shezen E, Hornstein E, Mandelboim O, Reisner Y, Benvenisty N. Human embryonic stem cells and their differentiated derivatives are less susceptible to immune rejection than adult cells. Stem Cells. 2006; 24:221–229. DOI: 10.1634/stemcells.2005-0188.

11. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992; 255:1707–1710. DOI: 10.1126/science.1553558. PMID: 1553558.

12. Shroff G. Establishment and characterization of a neuronal cell line derived from a 2-cell stage human embryo: clinically tested cell-based therapy for neurological disorders. International Journal of Recent Scientific Research. 2015; 6:3730–3738.

13. DAVID. [cited 2017 May 1]. Available from: https://david-d.ncifcrf.gov/.

14. KEGG. [cited 2017 Apr 18]. Available from: www.genome.ad.jp/kegg.

15. Panther. [cited 2017 May 11]. Available from: http://pantherdb.org/.

16. Reactome. [cited 2017 May 5]. Available from: http://www.reactome.org.

17. Odorico JS, Kaufman DS, Thomson JA. Multilineage differentiation from human embryonic stem cell lines. Stem Cells. 2001; 19:193–204. DOI: 10.1634/stemcells.19-3-193.

18. Rogers NJ, Lechler RI. Allorecognition. Am J Transplant. 2001; 1:97–102. DOI: 10.1034/j.1600-6143.2001.10201.x.

19. Drukker M. Immunogenicity of human embryonic stem cells: can we achieve tolerance? Springer Semin Immunopathol. 2004; 26:201–213. DOI: 10.1007/s00281-004-0163-5. PMID: 15549307.

20. Li L, Baroja ML, Majumdar A, Chadwick K, Rouleau A, Gallacher L, Ferber I, Lebkowski J, Martin T, Madrenas J, Bhatia M. Human embryonic stem cells possess immune-privileged properties. Stem Cells. 2004; 22:448–456. DOI: 10.1634/stemcells.22-4-448. PMID: 15277692.

21. Dekel B, Burakova T, Arditti FD, Reich-Zeliger S, Milstein O, Aviel-Ronen S, Rechavi G, Friedman N, Kaminski N, Passwell JH, Reisner Y. Human and porcine early kidney precursors as a new source for transplantation. Nat Med. 2003; 9:53–60. DOI: 10.1038/nm812.

22. Shroff G. Human embryonic stem cell for the treatment of multiple sclerosis: A case report. Case Rep Int. 2015; 4:38–42.

23. Shroff G. Therapeutic potential of human embryonic stem cells in type 2 diabetes mellitus. World J Stem Cells. 2016; 8:223–230. DOI: 10.4252/wjsc.v8.i7.223. PMID: 27468331. PMCID: 4958687.

24. Shroff G, Das L. Human embryonic stem cell therapy in cerebral palsy children with cortical visual impairment: a case series of 40 patients. J Cell Sci Ther. 2014; 5:189.

25. Shroff G, Gupta R. Human embryonic stem cells in the treatment of patients with spinal cord injury. Ann Neurosci. 2015; 22:208–216. DOI: 10.5214/ans.0972.7531.220404. PMID: 26526627. PMCID: 4627203.

26. Shroff G, Gupta R, Zadeng L. Human embryonic stem cell therapy for aplastic anemia. Clin Case Rep. 2017; 5:919–922. DOI: 10.1002/ccr3.950. PMID: 28588839. PMCID: 5458044.