Current and future perspectives on allogeneic transplantation using ex vivo expansion or manipulation of umbilical cord blood cells

Maung, Ko Ko; Horwitz, Mitchell E.

doi:10.1007/s12185-019-02670-6

Cited by 21 publications

(12 citation statements)

References 43 publications

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“…By manipulating UCB units to increase their cell yield, the drawbacks of single unit transplants (such as increased graft failure and delayed immune reconstitution) can potentially be surpassed ( Kelly et al, 2009 ). Multiple strategies have been developed toward achieving a successful expansion, with several reaching phase III clinical trial level ( Maung and Horwitz, 2019 ). Approaches have varied from promoting HSPC expansion with novel small molecules including StemRegenin-1 ( Wagner et al, 2016 ), UM171 ( Fares et al, 2014 ), and nicotinamide ( Horwitz et al, 2014 ), co-culture with mesenchymal stromal cells ( de Lima et al, 2012 ) and induction of Notch signaling pathways ( Delaney et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Tailored Cytokine Optimization for ex vivo Culture Platforms Targeting the Expansion of Human Hematopoietic Stem/Progenitor Cells

Branco

Bucar

Moura-Sampaio

et al. 2020

Front. Bioeng. Biotechnol.

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Umbilical cord blood (UCB) has been established as an alternative source for hematopoietic stem/progenitor cells (HSPC) for cell and gene therapies. Limited cell yields of UCB units have been tackled with the development of cytokine-based ex vivo expansion platforms. To improve the effectiveness of these platforms, namely targeting clinical approval, in this study, we optimized the cytokine cocktails in two clinically relevant expansion platforms for HSPC, a liquid suspension culture system (CS_HSPC) and a co-culture system with bone marrow derived mesenchymal stromal cells (BM MSC) (CS_HSPC/MSC). Using a methodology based on experimental design, three different cytokines [stem cell factor (SCF), fms-like tyrosine kinase 3 ligand (Flt-3L), and thrombopoietin (TPO)] were studied in both systems during a 7-day culture under serum-free conditions. Proliferation and colony-forming unit assays, as well as immunophenotypic analysis were performed. Five experimental outputs [fold increase (FI) of total nucleated cells (FI TNC), FI of CD34 + cells, FI of erythroid burst-forming unit (BFU-E), FI of colony-forming unit granulocyte-monocyte (CFU-GM), and FI of multilineage colony-forming unit (CFU-Mix)] were followed as target outputs of the optimization model. The novel optimized cocktails determined herein comprised concentrations of 64, 61, and 80 ng/mL (CS_HSPC) and 90, 82, and 77 ng/mL (CS_HSPC/MSC) for SCF, Flt-3L, and TPO, respectively. After cytokine optimization, CS_HSPC and CS_HSPC/MSC were directly compared as platforms. CS_HSPC/MSC outperformed the feeder-free system in 6 of 8 tested experimental measures, displaying superior capability toward increasing the number of hematopoietic cells while maintaining the expression of HSPC markers (i.e., CD34 + and CD34 + CD90 +) and multilineage differentiation potential. A tailored approach toward optimization has made it possible to individually maximize cytokine contribution in both studied platforms. Consequently, cocktail optimization has successfully led to an increase in the expansion platform performance, while allowing a rational side-by-side comparison among different platforms and enhancing our knowledge on the impact of cytokine supplementation on the HSPC expansion process.

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Section: Introductionmentioning

confidence: 99%

Tailored Cytokine Optimization for ex vivo Culture Platforms Targeting the Expansion of Human Hematopoietic Stem/Progenitor Cells

Branco

Bucar

Moura-Sampaio

et al. 2020

Front. Bioeng. Biotechnol.

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“…The main challenge in the clinical application of bone marrow or HSC transplantation would be the availability of young, suitably matched donors. Cord blood is a potential source of young HSCs, but supplies are limited, and two cords are currently required for transplantation in adults, although methods to expand cord blood stem cells are improving 17 . An alternative strategy may be to rejuvenate a patient's own cells by reprogramming them to pluripotency (induced pluripotent stem cells, iPSCs), which would erase aging-associated epigenetic marks, and then re-differentiate iPSCs to HSCs.…”

Section: Young Bone Marrow or Hsc Transplantationmentioning

confidence: 99%

Rejuvenating the blood and bone marrow to slow aging-associated cognitive decline and Alzheimer’s disease

et al. 2020

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Parabiosis, blood exchange and plasma transfer experiments have highlighted the rejuvenating properties of young blood. Our Communications Biology study demonstrated that young bone marrow transplantation attenuates cognitive decline in old mice, with preservation of hippocampal synapses and reduced microglial reactivity. We now discuss subsequent studies that shed additional light on how blood impacts cognitive function, and potential clinical applications, including ongoing clinical trials with young plasma and experimental strategies targeting the hematopoietic system to slow or reverse cognitive decline. Preservation and rejuvenation of cognition during aging by young blood Cumulative evidence from parabiosis, blood exchange and plasma transfer experiments has demonstrated that young blood can rejuvenate multiple organs in old mice, including the brain, liver, muscle, and heart, and that old blood accelerates aging in young mice (reviewed in refs. 1,2). Heterochronic parabiosis studies, in which old and young mice are surgically joined so they share a circulatory system, have suggested that circulating components of young blood can induce brain rejuvenation in old parabionts, including improvement of hippocampal learning and memory (reviewed in ref. 3). A single blood exchange between old and young mice (without organ sharing, which might confound parabiosis experiments) had similar outcomes 4 , and plasma transfer experiments implicated soluble factors in the circulation 5,6. Together these studies suggest that young and old blood contain varying levels of youthful and pro-aging factors, and that manipulation of those factors represents a promising therapeutic approach for the treatment of human aging-associated diseases such as Alzheimer's disease 7 .

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“…Recently, a role for MΦ-derived PGE2 in facilitating erythropoietin-induced erythropoiesis was reported by Chen et al 33 . Clinical trials have evaluated the ex vivo stimulation of human cord blood with the long-acting PGE2 analog dimethyl-PGE2 (dmPGE2) as a strategy to enhance engraftment 34 . Ex vivo stimulation avoids the potential for off-target dmPGE2-induced toxicity, however, our data together with the radioprotective and erythropoiesis-promoting effects of PGE2 26,27,33 , demonstrate the potential for additional benefit from strategies to elevate tissue PGE2 levels in transplant recipients.…”

Section: -Pgdh Localization and Enzymatic Activity Is Conserved In mentioning

confidence: 99%

15-PGDH Inhibition Activates the Splenic Niche to Promote Hematopoietic Regeneration

Smith

Dawson

Christo

et al. 2020

Preprint

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The splenic microenvironment regulates hematopoietic stem and progenitor cell (HSPC) function, particularly during demand-adapted hematopoiesis, however practical strategies to enhance splenic support of transplanted HSPCs have proven elusive. We have previously demonstrated that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using the small molecule (+)SW033291 (PGDHi), increases bone marrow (BM) prostaglandin E2 (PGE2) levels, expands HSPC numbers, and accelerates hematologic reconstitution following BM transplantation (BMT) in mice. Here we demonstrate that the splenic microenvironment, specifically 15-PGDH high-expressing macrophages (MΦs), megakaryocytes (MKs), and mast cells (MCs), regulates steady-state hematopoiesis and potentiates recovery after BMT. Notably, PGDHi-induced neutrophil, platelet, and HSPC recovery were highly attenuated in splenectomized mice. PGDHi induced non-pathologic splenic extramedullary hematopoiesis at steady-state, and pre-transplant PGDHi enhanced the homing of transplanted cells to the spleen. 15-PGDH enzymatic activity localized specifically to MΦs, MK lineage cells, and MCs, identifying these cell types as likely coordinating the impact of PGDHi on splenic HSPCs. These findings suggest that 15-PGDH expression marks novel HSC niche cell types that regulate hematopoietic regeneration. Therefore, PGDHi provides a well-tolerated strategy to therapeutically target multiple HSC niches and to promote hematopoietic regeneration and improve clinical outcomes of BMT.

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Current and future perspectives on allogeneic transplantation using ex vivo expansion or manipulation of umbilical cord blood cells

Cited by 21 publications

References 43 publications

Tailored Cytokine Optimization for ex vivo Culture Platforms Targeting the Expansion of Human Hematopoietic Stem/Progenitor Cells

Tailored Cytokine Optimization for ex vivo Culture Platforms Targeting the Expansion of Human Hematopoietic Stem/Progenitor Cells

Rejuvenating the blood and bone marrow to slow aging-associated cognitive decline and Alzheimer’s disease

15-PGDH Inhibition Activates the Splenic Niche to Promote Hematopoietic Regeneration

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