Careful You May Be Stuck with the Cell’s Phenotype and Genotype for a Very Long Time
Hematopoietic stem and progenitor cells (HSPCs) are responsible for generating and maintaining the extremely diverse pool of blood cells, everything from red blood cells to T-cells, for our lifetime. HSPC transplantation, also known as bone marrow transplantation, remains the only approved stem cell therapy, even though unapproved stem cell transplants for a variety of other indications continue to burgeon. The approved, clinical transplantation of human HSPCs from an allogeneic healthy donor can effectively replenish defective blood cell production caused by congenital or acquired disorders, but, as with most medical products or procedures, there are risks involved. Many case studies have reported the approved stem cell transplants to be associated with the later development of cancer (Cooley et al, 2000), and unapproved stem cell transplant procedures are notorious for side-effects, including development of cancer (Diouhy et al, 2014). Unfortunately, with most drugs and many medical procedures, the long term consequences to health are unknown. Often, when considering drugs, not until Phase IV, postmarket approval are the long term consequence of a drug discovered. Witness the many drugs pulled from market some three to four years after their approval (e.g. ProCon, 2014). Even more unfortunate, the problem is worse with medical procedures (Kumar and Nash, 2011). Such is the case with approved stem cell transplants. The effects of approved stem cell transplants in causing, or being involved, in cancer relapse are not well understood, but are thought to involve epigenetic factors in the stem cells used for the transplant (Christopher et al, 2018). In addition, any type of stem cell transplant may cause aging of the tissue as measured in T-cells using a p16 biomarker (Wood et al, 2016), indicating the increased level of cellular senescence in the surrounding tissue.
So what are some of the possible mechanisms for stem cells to cause these untoward and unpropitious side effects? First, a new study shows that transplanted stem cells (HSPCS) can survive a long time in human patients, such that they can be maintained independently of their continuous production from endogenous HSPCs (Scala et al, 2018). Second, we know that processed stem cells can carry an increasing number of genetic mutations as they are expanded, particularly the p53 mutation associated with many cancer phenotypes (Merkle et al, 2017). And, as I discussed in a previous blog, stem cells have memory, and change their phenotype, for at least many months, when they have experienced a wounding, inflammatory event (Naik et al, 2017). The new phenotype that Naik et al (2017) measured was one of an increased probability to proliferate, a cancer-like cellular behavior. An underlying mechanism for the increased probability of proliferation appeared to be epigenetic, where the DNA was less tightly bound around its histone protein. If we synthesize these data, stem cell transplants using cells that have genotypic, epigenotypic, and phenotypic changes conducive to proliferation, and given the cells ability to engraft, survive, and remain viable for long periods, means that the cells may be a cause of cancer. Coupled with the possible induction of aging in the surrounding tissue (Wood et al, 2016), another risk factor for cancer, stem cell transplants pose a significant risk for cancer, as well as other problems (Maguire, 2016). As such, the problems with stem cell transplants means they should only be used in life threatening conditions, or where their benefits clearly outweigh the risks. The problems with stem cell transplants also leads to the argument for the use of a “systems therapeutic” using stem cell released molecules (Maguire, 2014), instead of the cells (Maguire, 2013), for many indications, such as amytrophic lateral sclerosis and other neurodegenerative diseases (Maguire, 2018).
These issues will be further explored in my second book to be published in 2019.
Christopher MJ et al (2018) Immune Escape of Relapsed AML Cells after Allogeneic Transplantation. N. Eng. J. Med, DOI: 10.1056/NEJMoa1808777
Cooley LD et al (2000) Donor cell leukemia: report of a case occurring 11 years after allogeneic bone marrow transplantation and review of the literature. Am.J. Hematol. 63(1):46-53.
Diouhy BJ et al (2014) Autograft-derived spinal cord mass following olfactory mucosal cell transplantation in a spinal cord injury patient. J. Neurosurgery, DOI: https://doi.org/10.3171/2014.5.SPINE13992
Kumar S and Nash DB (2011) Health Care Myth Busters: Is There a High Degree of Scientific Certainty in Modern Medicine? Scientific American, March 25, 2011.
Maguire G (2013) Stem cell therapy without the cells. Commun Integr Biol. 6(6):e26631
Maguire G (2014) Systems biology approach to developing “systems therapeutics”. ACS Med. Chem. Lett. 5(5): 453–455
Maguire G (2016) Therapeutics from Adult Stem Cells and the Hype Curve. ACS Med. Che. Lett. 7(5):441-3
Maguire G (2018) Adult Stem Cell Released Molecules: A Paradigm Shift to Systems Therapeutics. Nova Science Publishers, New York.
Merkle FT et al (2017) Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations. Nature 545: 229–233
Naik S et al (2017) Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550: 475–480
ProCon (2014) 35 FDA-Approved Prescription Drugs Later Pulled from the Market. ProCon, Jan 30, 2014.
Scala S et al (2018) Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans. Nature Medicine 24:1683–1690
Wood WA et al (2016) Chemotherapy and Stem Cell Transplantation Increase p16INK4aExpression, a Biomarker of T-cell Aging. EBioMedicine, 11: 227–238