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Adult Stem Cells

Successful Standard for Regenerative Medicine
Originally publishedhttps://doi.org/10.1161/CIRCRESAHA.118.313664Circulation Research. 2019;124:837–839

    Adult stem cells are the successful standard for stem cells. Although in the past their regenerative/reparative capacity was ignored, misunderstood, or even maligned, a rapidly growing host of clinical applications are being developed, and the clinical utility of adult stem cells is increasingly validated in the literature.

    Adult stem cells are the true gold standard in regenerative medicine. Adult stem cells are the only stem cell type that has shown evidence of success when it comes to patients, and treating patients is supposedly the ultimate goal for stem cell research, certainly the justification for the huge sums of money poured into the field. By the end of 2012, over 1 million people around the globe had already received adult stem cell transplants for hematopoietic conditions alone, and adult stem cell clinical use is increasing rapidly.1 And because adult stem cells are noncontroversial, they are distinctly advantaged as acceptable to all patients. Yet, these most valuable of stem cells for the patient, despite evidence of success in the clinic, have been relatively unrecognized for their true value in medicine.

    In contrast, embryonic stem cells have received a great deal of attention despite their highly controversial nature and potential for clinical use. Certainly part of the controversy relates to their derivation, which involves the destruction of human embryos. A significant proportion of Americans, because of religious or personal conviction, attach moral worth to nascent human life and reject its destruction. Indeed, even the founder of the field of human embryonic stem cell research, Dr James Thomson, has said that “If human embryonic stem cell research does not make you at least a little bit uncomfortable, you have not thought about it enough.”2

    Beyond the significant ethical tensions around embryonic stem cells, there are a number of pragmatic concerns and problems that make them ill-suited for clinical use. Differentiation into physiologically relevant cell types that can integrate into damaged tissues and function normally has been difficult to achieve; for example, reports show difficulty achieving mature erythrocytes containing β-globin,3 as well as mature neuronal and hepatic cells.4 In animal models, embryonic stem cell–derived cardiomyocytes have shown evidence of causing arrhythmia.5 Immunogenicity is also a longstanding problem with embryonic stem cells and has even been noted as a problem for embryonic stem cells isolated from cloned embryos.6 Theoretically, cells from an embryo created by cloning (somatic cell nuclear transfer) were thought to be an immunologic match, but the evidence suggests that the so-called therapeutic cloning technique, although producing cells with the same DNA as the nuclear donor, is critically flawed in production of immunologically matching stem cells.

    The most significant concern regarding clinical use of embryonic stem cells is their potential tumorigenicity. This might not be surprising given their inherent capacity for rapid proliferation and because the standard for assessing pluripotency is teratoma formation, but numerous references note that they also accumulate mutations and chromosomal aberrations in culture.7 In some respects, such as expression of Myc and related genes, embryonic stem cells are more akin to cancer cells than to regenerative/reparative cells.8 Their inherent tendency for proliferation and tumorigenicity makes a worrying, perhaps insurmountable, hurdle to their clinical application.

    Nonembryonic stem cell research has surpassed embryonic stem cells. Induced pluripotent stem (iPS) cells, which show the same pluripotent characteristics,9 have replaced embryonic stem cells in many laboratories and are now the most prevalent pluripotent stem cell in published research studies (Figure).10,11 The Nobel-prize-winning iPS cells have distinct advantages compared with embryonic stem cells because they can be made from virtually any person or tissue, healthy or diseased, more cheaply and efficiently than embryonic stem cells and without the ethical concerns about their creation and isolation. Because they can be made from a patient, they represent the possibility for production of pluripotent-derived patient-matched cells for therapeutic reintroduction to the patient. However, great caution is warranted because iPS cells, as with embryonic stem cells, also show genetic instability in culture and may thus show tumorigenic potential.12 The advantages of iPS cells may be better utilized as pluripotent cells in their modeling of normal and abnormal cell growth and behavior, including as models (disease in a dish). They have already been successfully deployed to model various syndromes and determine causative pathways. As just 2 examples of their modeling prowess, the ability of iPS cells to follow normal developmental pathways and produce 3-dimensional organoids has been used to discover the mechanism of action of Zika virus on developing brains that results in microcephaly13and to dissect cellular problems associated with lissencephaly.14

    Figure.

    Figure. Number of original research papers in human pluripotent stem cell research. Trend in research activity by year, by comparison of worldwide research papers using hESC (human embryonic stem cells) vs hiPSC (human induced pluripotent stem cells) per year, 2006 to 2016 (hiPSC first created in 2006).

    Adult stem cells, however, are the gold standard for clinical applications and are being tested and accepted for a growing number of conditions. Not only do adult stem cells carry no ethical baggage regarding their isolation, their practical advantages over pluripotent stem cells have led to many current clinical trials, as well as some therapies approved through all phases of Food and Drug Administration testing. Peer-reviewed, published successful results abound, with numerous papers now documenting therapeutic benefit in clinical trials and progress toward fully tested and approved treatments. Phase I/II trials suggest potential cardiovascular benefit from bone marrow–derived adult stem cells and umbilical cord blood–derived cells.15 Striking results have been reported using adult stem cells to treat neurological conditions, including chronic stroke.16 Positive long-term progression-free outcomes have been seen, including some remission, for multiple sclerosis,17 as well as benefits in early trials for patients with type I diabetes mellitus and spinal cord injury.18 And adult stem cells are starting to be used as vehicles for genetic therapies, such as for epidermolysis bullosa.19

    The progress of adult stem cells toward the clinic has been uneven and slower than many had hoped. The classical paradigm for stem cell growth and differentiation has been that of the hematopoietic stem cell, with defined factors inducing steps in differentiation evidenced by expression of different cell surface markers. However, this rigid hierarchy cannot explain or reconcile the data showing regeneration or repair of tissues other than bone marrow, especially across different primary germ layers. Likewise attempts to define stemness (the character of being a stem cell) by expression of a common set of genes helped position embryonic stem cells into an overall hierarchical paradigm for differentiation but failed to define a common stem cell gene set for all adult stem cells or to explain the regenerative/reparative capacity of adult stem cells. The resistance to the idea of nonhierarchical plasticity and repair by adult stem cells led to various attempts to devalue their regenerative/reparative potential, as well as calls for proof of stemness before clinical applications move forward. Yet as pointed out again and again,15 old paradigms do not explain the data showing repair of various tissues by adult stem cells, contrasted with newer ideas that the true definition of adult stem cells may be best based on function rather than cell markers—an idea that was pointed out previously.20 Modern medical science calls for modern concepts.

    The superiority of adult stem cells in the clinic and the mounting evidence supporting their effectiveness in regeneration and repair make adult stem cells the gold standard of stem cells for patients.

    Footnotes

    The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

    Correspondence to David A. Prentice, PhD, Charlotte Lozier Institute, 2800 Shirlington Rd, Suite 1200, Arlington, VA 22206. Email

    References

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