Levels of Repair Inducible with Induced Pluripotent Stem Cells (iPS Cells)

Induced pluripotent stem cells can be strategically utilized at several biological levels, as described below.

Each of these levels of repair at which iPSCs can exert their effects are considered in greater detail below.

1. Gene-Level Repair (Gene Therapy)

An advantage of induced pluripotent stem cells over other transplant approaches is the ability to repair disease-causing mutations using gene targeting and correction technologies.¹

An example of the use of iPSCs to treat disease through the correction of the underlying defect include a mouse model of sickle cell anemia where the wild-type β-globin gene was used to replace the defective gene by homologous recombination. Transplantation with genetically corrected iPSC-derived hematopoietic progenitors was then successful in improving symptoms of anemia and physiological function.²

Likewise, in humans with Fanconi anemia, a disease characterized by extreme genetic instability, the mutant gene was replaced using lentiviral vectors prior to epigenetic reprogramming of the patient’s fibroblasts and keratinocytes, because the genetic instability of the mutant fibroblasts made them non-permissive for iPSC generation. Interestingly, these iPSCs could be differentiated into hematopoietic progenitors as efficiently as wild-type iPSCs, stably maintaining the disease-free phenotype in vitro.³

2. Cellular Repair (Cell Replacement Therapy)

Another approach for using iPSC in cellular therapy is to employ mature cell types differentiated from iPSCs.  To date, this approach has been most often explored with hepatocytes derived from human induced pluripotent stem cells.  Hepatocytes are the main functional cells of the liver and perform critical endocrine and exocrine functions, but research utilizing human hepatocytes for cellular transplantation has been limited by the difficulties in sourcing and maintaining viable hepatocytes.⁴

Nonetheless, a number of cell-based and animal-model studies of human liver disorders have revealed the extreme regenerative capacity of hepatocytes in vivo, indicating that hepatocyte transplantation may represent a viable strategy for replacing damaged or diseased hepatic tissue.⁵  Transplantation of hepatocytes derived from human induced pluripotent stem cells could therefore represent an alternative to liver transplantation, as well as a method for correcting genetic disorders of the liver.⁶

In theory, the approach of repairing damaged or diseased tissue with differentiated cells derived from human induced pluripotent stem cells could be applied to any cell type within the human body.

3. iPSC-Derived Blood Products

Another approach for therapeutically applying iPSCs is to create iPSC-derived blood products.  A leader in this area is Megakaryon Corporation, a venture company founded in 2013 through the collaboration of individual and corporate members associated with Tokyo University and Kyoto University.⁷  The company produces technologies for the production of iPS cell derived human platelets, red blood cells and T cells and sells them globally.

Platelets and the red blood cells derived from iPS cells have the potential to be used as the blood products, without requiring blood donations from donors, while Leukocyte T cells derived from iPSCs may be used in the management of diseases that may include AIDS, cancer, hepatitis, and more.

4. Whole Tissue Repair (Organ Replacement Therapy)

Currently, the standard of care for terminal organ failure is orthotopic⁸ transplantation.  However, the demand for transplantation far exceeds the number of available donor organs, which has driven tissue-engineering/regenerative-medicine approaches for creating functional organ replacements to be developed.

A possible  use of iPSC to regenerate tissues and organs is in engineering a whole organ using decellularization of matrix bioscaffolds and recellularization with iPSCs.⁹   Decellularization and recellularization of matrix bioscaffolds has been shown to be a promising approach for whole-organ tissue engineering in recent years with other stem cell types, although it has not yet been accomplished with iPSCs.¹⁰

Thus far, it has been shown that donor organs including the lung¹¹, liver¹², heart¹³, kidney¹⁴, and bladder¹⁵ can be successfully decellularized to an acellular biologic scaffold material and then be recellularized with selected stem and progenitor cell populations.  Preliminary studies in animal models have provided encouraging results for the proof of concept that these three-dimensional scaffolds can be successfully re-populated.

Extrapolating these findings, it can be assumed that decellularization of donor organs to provide an acellular, naturally occurring three-dimensional biologic scaffold material would allow for it to be seeded with induced pluripotent stem cells to facilitate functional organ replacements.  This medical possibility is likely to be a near-term reality.

In addition, proof of principle examples have demonstrated that it is possible to generate fully functional organs from a single adult stem cell.^16,17,18 While this has not yet been accomplished with induced pluripotent stem cells, it has been accomplished with other stem cell types.  For instance, it has been elegantly demonstrated by independent research teams that the mammary gland and the prostate can be generated in vivo from a single adult tissue stem cell. The ability to perform this technique with iPSCs may also be possible.

Finally, other methods of stem cell-derived full organ generation exist as well, such as generation of organs using a blastocyst complementation system.  Specifically, embryonic stem cells (ESCs) have been shown to be able to produce specific organs by using a strategy of injection of embryonic stem cells from one species into the blastocyst of another species.

References
1.    Singh, et al. Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. Front Cell Dev Biol. 2015;
2. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science. 2007;318:1920–3
3.    Raya A, Rodriguez-Piza I, Guenechea G. et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature.  2009; 460: 53–9.
4.    Yong Soon Chun, et al. “Applications of Patient-Specific Induced Pluripotent Stem Cells; Focused on Disease Modeling, Drug Screening and Therapeutic Potentials for Liver Disease.” Int J Biol Sci. 2010; 6(7): 796–805. Published Online December 14, 2010. Accessed April 1, 2013.
5.    Overturf K, al-Dhalimy M, Ou CN. et al. Serial transplantation reveals the stem-cell- like regenerative potential of adult mouse hepatocytes. Am J Pathol. 1997;151:1273–80.
6.    Seifinejad A, Tabebordbar M, Baharvand H. et al. Progress and promise towards safe induced pluripotent stem cells for therapy. Stem Cell Rev and Rep. 2010;6:297–306.
7.    Megakaryon.com,. ‘Megakaryon Corporation’. N.p., 2015. Web. 8 Apr. 2015.
8.    Orthotopic means at the naturally occurring place.
9.    Yunying Liu, et al. “Generation of functional organs from stem cells.”  Cell Regeneration 2013, 2:1 doi:10.1186/2045-9769-2-1. Available at: http://www.cellregeneration.journal.com/content/2/1/1.
10.    Ibid.
11.    Petersen TH, Calle EA, Zhao L, Lee EJ, Gui L, Raredon MB, Gavrilov K, Yi T, Zhuang ZW, Breuer C, Herzog E, Niklason  LE: Tissue-engineered lungs for in vivo implantation. Science 2010, 329(5991):538-541.
12.    Uygun BE, Soto-Gutierrez A, Yagi H, Izamis ML, Guzzardi MA, Shulman C, Milwid J, Kobayashi N, Tilles A, Berthiaume F, Hertl M, Nahmias Y, Yarmush ML, Uygun K: Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med 2010, 16(7):814-820.
13.    Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA: “Perfusion-decellularized matrix: using nature’s  platform to engineer a bioartificial heart.” Nat Med 2008, 14(2):213-221.
14.    Ross EA, Williams MJ, Hamazaki T, Terada N, Clapp WL, Adin C, Ellison GW, Jorgensen M, Batich CD: “Embryonic stem cells proliferate and differentiate when seeded into kidney scaffolds.” J Am Soc Nephrol 2009, 20(11):2338-2347.
15.    Rosario DJ, Reilly GC, Ali Salah E, Glover M, Bullock AJ, Macneil S: “Decellularization and sterilization of porcine bladder  matrix for tissue engineering in the lower urinary tract.” Regen Med 2008, 3(2):145-156.
16.    Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, Wu L, Lindeman GJ, Visvader JE: Generation of a functional mammary gland from a single stem cell. Nature 2006, 439(7072):84-88.
17.    Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, Li HI, Eaves CJ:Purification and unique properties of mammary epithelial stem cells. Nature 2006, 439(7079):993-997
18.    Leong KG, Wang BE, Johnson L, Gao WQ: Generation of a prostate from a single adult stem cell. Nature 2008, 456(7223):804-808. Epub 2008 Oct 22.

To learn more about the rapidly expanding market for iPSCs, view the “Global Induced Pluripotent Stem Cell (iPS Cell) Industry Report 2022.”