Purified Hematopoietic Stem Cell Transplantation: The Next Generation of Blood and Immune Replacement

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Advantages of purified allogeneic hematopoietic stem cell transplantation

HSCs are the only cells within the body that at a clonal level have the ability to self-renew for life as well as give rise to all the different distinct mature effectors cells that comprise the blood and immune system.1 These 2 properties give HSCs the sole responsibility for the proper lifelong maintenance of hematopoietic homeostasis. However, genetic abnormalities within HSCs can result in diseases such as immunodeficiency, autoimmunity, hemoglobinopathies, or hematologic malignancies, as

Application of HSCT: curing a variety of nonmalignant hematolymphoid diseases

Toxicity associated with HCT has dramatically restricted its current practice to life-threatening disorders such as hematologic malignancies and bone marrow failure states, where few other therapeutic options exist. However, HCT has other important potential applications beyond its current uses if HCT-associated toxicity could be eliminated. HCT has been shown to effectively reverse nonmalignant genetic hematologic disorders such as sickle cell anemia and β-thalassemia, as well as primary

Barriers to expansion of HSCT

Continued improvements in the control of regimen-related toxicities are necessary to expand the applications of HCT. Current HCT methods hold exorbitant risk to the patient in terms of the transplant procedure–related morbidity and mortality, providing a major impediment to extrapolation of these practices to a multitude of conditions.

Although GvHD may be eliminated by transplantation of purified HSCs, much toxicity of HCT is also attributable to the conditioning regimens necessary to enable

Up-and-coming strategies to improve HSCT

HSCs are migratory cells.65 Under homeostatic conditions they can be found in blood circulation in addition to bone marrow, albeit at very low but physiologically relevant frequency.66 Recent studies have shown that HSCs enter the blood stream via division-independent egress from the bone marrow, leaving behind empty HSC niches available for transplantation, and explaining why low levels of engraftment are observed in nonconditioned settings.66 HSCs continually egress from the marrow and enter

Revolutionizing HCT

Almost 60 years has passed since the early dismal but promising transplants performed by Thomas and colleagues,72 and since then we have learned much about the biology of blood and immune transplantation. Yet today we still face many of the same hurdles faced by our predecessors, namely, the competing challenges of (1) complications arising from GvHD syndrome and (2) toxicities associated with preparative regimens necessary for cell engraftment.

Recent data suggest we may be bordering on

Acknowledgments

The authors thank D. Bhattacharya and M. Howard for insightful review of the manuscript.

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    This investigation was supported by National Institutes of Health grants R01CA086065 and R01HL058770 (to I.L.W.). A.C. is supported by the Medical Scientist Training Program at Stanford University School of Medicine, as well as a grant from The Paul and Daisy Soros Fellowships for New Americans. The program is not responsible for the views expressed.

    Affiliations that might be perceived to have biased this work are as follows: I.L.W. cofounded and consulted for Systemix, is a cofounder and director of Stem Cells, Inc, and cofounded and is a former director of Cellerant, Inc. A.C. declares no financial or commercial conflict of interest.

    A version of this article was previously published in the Immunology and Allergy Clinics of North America, 30:2.

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