Clinical-scale human umbilical cord blood cell expansion in a novel automated perfusion culture system

Koller, Manfred R.; Manchel, Ilana; Maher, Robert J.; Goltry, Kristin L.; Armstrong, R.D.; Smith, A. K.

doi:10.1038/sj.bmt.1701157

Cited by 99 publications

(46 citation statements)

References 21 publications

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“…Our group also expanded unfractionated UCB cells in the Aastrom/Replicell system as described above. 22,23 We reported a 2.4-fold increase in TNC expansion, but a loss of 36% of CD34 þ cells and a similar loss of LTC-IC of 40%. Engraftment was not enhanced in our patients nor in another trial where expanded cells were infused also on day 12.…”

Section: Early Clinical Experience Of Hsc Ex Vivo Expansionmentioning

confidence: 98%

Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche

Hofmeister

Zhang

Knight

et al. 2006

Bone Marrow Transplant

199

172

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Umbilical cord blood transplantation (UCBT) in adults is limited by the small number of primitive hematopoietic stem cells (HSC) in each graft, resulting in delayed engraftment post transplant, and both short-and longterm infectious complications. Initial efforts to expand UCB progenitors ex vivo have resulted in expansion of mature rather than immature HSC, confounded by the inability to accurately and reliably measure long-term reconstituting cells. Ex vivo expansion of UCB HSC has failed to improve engraftment because of resulting defects that promote apoptosis, disrupt marrow homing and initiate cell cycling. Here we discuss the future of ex vivo expansion, which we suggest will include the isolation of immature hematopoietic progenitors on the basis of function rather than surface phenotype and will employ both cytokines and stroma to maintain and expand the stem cell niche. We suggest that ex vivo expansion could be enhanced by manipulating newly discovered signaling pathways (Notch, Wnt, bone morphogenetic protein 4 and Tie2/angiopoietin-1) and intracellular mediators (phosphatase and tensin homolog and glycogen synthase kinase-3) in a manner that promotes HSC expansion with less differentiation. Improved methods for ex vivo expansion will make UCBT available to more patients, decrease engraftment times and allow more rapid immune reconstitution post transplant.

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Section: Early Clinical Experience Of Hsc Ex Vivo Expansionmentioning

confidence: 98%

Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche

Hofmeister

Zhang

Knight

et al. 2006

Bone Marrow Transplant

199

172

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“…Attempts to increase UCB cell dose has laid the basis for laboratory 56 and phase I clinical trials [57][58][59] focused on ex vivo expansion of UCB grafts. Although early clinical trials reported thus far do not point to more rapid hematopoietic recovery in UCB recipients, there is improved day 100 survival compared with historical controls.…”

Section: Future Initiatives: Ucb Transplantationmentioning

confidence: 99%

Umbilical cord blood for allogeneic transplantation in children and adults

Laughlin

2001

Bone Marrow Transplant

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Summary:Early clinical reports outlining outcomes for primarily pediatric patients undergoing UCB transplantation, point to delayed time to hematopoietic recovery, and favorable incidence and severity of graft-versus-host disease. Intensive clinical and laboratory research is ongoing focused on strategies to foster UCB allogeneic donor engraftment, thereby allowing wider application of this stem cell source for patients requiring allogeneic transplantation. Bone Marrow Transplantation (2001) 27, 1-6. Keywords: umbilical cord blood; allogeneic transplantation Allogeneic blood and bone marrow stem cell transplantation is limited by the availability of suitable HLAmatched related donors. In 1988, umbilical cord blood (UCB) hematopoietic stem cells (HSC) from a related sibling were transplanted successfully into a child with Fanconi anemia. 1 Subsequently, UCB from HLA-mismatched related 2 and unrelated donors has been shown to successfully engraft pediatric 3-8 and a few reported adult patients 6,9-11 with hematologic malignancies, immunodeficiency syndromes, inborn errors of metabolism, or marrow failure syndromes. This article will review the use of UCB as a suitable alternative for allogeneic transplantation. Tables 1 and 2 outline the advantages and disadvantages for the application of UCB as a new source of HSC for patients requiring allogeneic transplantation. UCB collection and bankingSince the first successful unrelated UCB transplant was performed by J Kurtzberg and the pediatric transplant team at Duke University in 1993, 7 clinical and laboratory studies have burgeoned and standard operating procedures have been developed for the collection, processing, and storage of UCB units. [12][13][14][15][16][17][18][19] UCB collection is performed during the final phase of labor or, more commonly, after delivery of

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“…A continuous perfusion system [119] and, more recently, a fed-batch system [120] designed to reduce the accumulating negative cues during the culture of HSCs significantly enhanced the expansion of functional primitive HSCs. Both of decreasing the concentration of accumulating negative secreted factors and increasing culture volume to maintain a lower cell density benefits HSC expansion.…”

Section: Continuous Perfusion and Fed-batch Systemsmentioning

confidence: 99%

Ex vivo expansion of hematopoietic stem cells

Xie

Zhang

2015

Sci. China Life Sci.

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Ex vivo expansion of hematopoietic stem cells (HSCs) would benefit clinical applications in several aspects, to improve patient survival, utilize cord blood stem cells for adult applications, and selectively propagate stem cell populations after genetic manipulation. In this review we summarize and discuss recent advances in the culture systems of mouse and human HSCs, which include stroma/HSC co-culture, continuous perfusion and fed-batch cultures, and those supplemented with extrinsic ligands, membrane transportable transcription factors, complement components, protein modification enzymes, metabolites, or small molecule chemicals. Some of the expansion systems have been tested in clinical trials. The optimal condition for ex vivo expansion of the primitive and functional human HSCs is still under development. An improved understanding of the mechanisms for HSC cell fate determination and the HSC culture characteristics will guide development of new strategies to overcome difficulties. In the future, development of a combination treatment regimen with agents that enhance self-renewal, block differentiation, and improve homing will be critical. Methods to enhance yields and lower cost during collection and processing should be employed. The employment of an efficient system for ex vivo expansion of HSCs will facilitate the further development of novel strategies for cell and gene therapies including genome editing. ex vivo expansion, hematopoietic stem cells, niche, signal transduction, cord blood, transplantation, SCID-repopulating cell, genome editing, CRISPR/Cas9 Citation:Xie JJ, Zhang CC. Ex vivo expansion of hematopoietic stem cells.

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Clinical-scale human umbilical cord blood cell expansion in a novel automated perfusion culture system

Cited by 99 publications

References 21 publications

Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche

Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche

Umbilical cord blood for allogeneic transplantation in children and adults

Ex vivo expansion of hematopoietic stem cells

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