Purified Hematopoietic Stem Cell Transplantation: The Next Generation of Blood and Immune Replacement
Section snippets
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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2021, Blood AdvancesCitation Excerpt :Hematopoietic stem cells (HSCs) produce all blood lineages and replenish blood in response to loss or injury throughout life. Allogeneic HSC transplantation is curative in many blood disorders, as well as in some solid tumors and autoimmune disorders,1-6 yet long-term survival is limited because of a lack of sufficient genetically matched HSC donors.7 Umbilical cord blood (CB) offers an alternative source with several advantages, including immune tolerance for mismatched genetic background.8
Current approaches in biomaterial-based hematopoietic stem cell niches
2018, Acta BiomaterialiaGM-CSF and IL-4 Fusion Cytokine Induces B Cell-Dependent Hematopoietic Regeneration
2017, Molecular TherapyCitation Excerpt :As a portion of lineage-negative (Lin−), Sca-1 (stem cells antigen-1)-positive and c-Kit (CD117)-positive cells (LSK cells) containing hematopoietic stem and progenitor cell pool,3,4 HSCs primarily reside in a highly complex microenvironment of the bone marrow.5,6 Due to their hematopoietic-generating properties, HSCs and hematopoietic progenitor cells have been widely used as autologous or allogeneic transplants to treat patients with blood disorders and hematopoietic malignancies.7,8 However, following transplantation, patients may remain cytopenic and immune defective, with accrued mortality risk arising from engraftment failure, opportunistic infection, and disease relapse.9,10
Fetal Hematopoietic Stem Cell Transplantation Fails to Fully Regenerate the B-Lymphocyte Compartment
2016, Stem Cell ReportsCitation Excerpt :Since the initial purification and characterization of murine HSCs in 1988 (Spangrude et al., 1988), the phenotype and reconstitution potential of HSCs from both mice and humans have been extensively studied. Currently HSCs are widely used in human regenerative therapies to restore immunity in irradiated or otherwise immune-compromised patients (Czechowicz and Weissman, 2011; Liang and Zuniga-Pflucker, 2015; Pasquini and Zhu, 2014). However, relatively little is known about the scope of this reconstitution, particularly with respect to subsets of myeloid cells and lymphocytes (i.e., tissue B cells) that are not readily detectable in blood.
Nucleic acid delivery: Roles in biogerontological interventions
2013, Ageing Research ReviewsCitation Excerpt :Now cell replacement therapy for Parkinson's disease (an age-associated degenerative disorder characterized by muscle rigidity, bradykinesia, tremor and a progressive loss of dopamine neurons in the substantia nigra pars compacta) has been made feasible by using induced pluripotent cells derived from somatic cells (Chen et al., 2011). With hematopoietic cell transplantation, replacement of disease-causing stem cells with normal ones has also been made clinically possible during the last 40 years (Czechowicz and Weissman, 2011). These advances have illuminated the plausibility of confronting cell loss and tissue atrophy clinically.
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.