Gene products promoting remyelination are up-regulated in a cell therapy product manufactured from banked human cord blood

Scotland, Paula; Buntz, Susan; Noeldner, Pamela K.; Saha, Arjun; Gentry, Tracy; Kurtzberg, Joanne; Balber, Andrew E.

doi:10.1016/j.jcyt.2017.03.004

Cited by 3 publications

(2 citation statements)

References 53 publications

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“…reported that CB-MNC, but not PB-MNC, stimulated neurogenesis in aging rat brains [34]. CB, neonatal peripheral PB, and adult PB express different receptors, secrete different cytokines, and respond differently to inflammatory stimuli [35]. If these differences are reflected in the differential protective activity in the OGD assay remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Human umbilical cord blood monocytes, but not adult blood monocytes, rescue brain cells from hypoxic-ischemic injury: Mechanistic and therapeutic implications

Saha

Patel

et al. 2019

PLoS ONE

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Cord blood (CB) mononuclear cells (MNC) are being tested in clinical trials to treat hypoxic-ischemic (HI) brain injuries. Although early results are encouraging, mechanisms underlying potential clinical benefits are not well understood. To explore these mechanisms further, we exposed mouse brain organotypic slice cultures to oxygen and glucose deprivation (OGD) and then treated the brain slices with cells from CB or adult peripheral blood (PB). We found that CB-MNCs protect neurons from OGD-induced death and reduced both microglial and astrocyte activation. PB-MNC failed to affect either outcome. The protective activities were largely mediated by factors secreted by CB-MNC, as direct cell-to-cell contact between the injured brain slices and CB cells was not essential. To determine if a specific subpopulation of CB-MNC are responsible for these protective activities, we depleted CB-MNC of various cell types and found that only removal of CB CD14 + monocytes abolished neuroprotection. We also used positively selected subpopulations of CB-MNC and PB-MNC in this assay and demonstrated that purified CB-CD14 + cells, but not CB-PB CD14 + cells, efficiently protected neuronal cells from death and reduced glial activation following OGD. Gene expression microarray analysis demonstrated that compared to PB-CD14 + monocytes, CB-CD14 + monocytes over-expressed several secreted proteins with potential to protect neurons. Differential expression of five candidate effector molecules, chitinase 3-like protein-1, inhibin-A, interleukin-10, matrix metalloproteinase-9 and thrombospondin-1, were confirmed by western blotting, and immunofluorescence. These findings suggest that CD14 + monocytes are a critical cell-type when treating HI with CB-MNC.

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Section: Discussionmentioning

confidence: 99%

Human umbilical cord blood monocytes, but not adult blood monocytes, rescue brain cells from hypoxic-ischemic injury: Mechanistic and therapeutic implications

Saha

Patel

et al. 2019

PLoS ONE

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“…We did not target CD34 dosing in this clinical trial because our preclinical studies and early-phase clinical trial data in children with ASD and children with cerebral palsy (CP) did not show any association between improvement and CD34 dosing.Our data showed that the cell responsible for modulation of neuroinflammation, stimulation of oligodendrocyte proliferation, remyelination, and increasing whole brain connectivity is the CD14+ monocyte in cord blood. [1][2][3][4] Cord blood banks do not measure CD14 cell content but do measure total nucleated cells (TNCCs) and CD34. For this reason, selection of cord blood units for the participants with ASD and CP in our clinical trials has been based on TNCC.…”

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confidence: 99%

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Dawson¹,

Kurtzberg

2021

The Journal of Pediatrics

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ogous cord blood infusions are safe and feasible in young children with autism spectrum disorder: results of a single-center phase I open-label trial. Stem Cells Transl Med 2017;6:1332-9. ReplyTo the Editor:We appreciate the questions raised by Thanh et al about our clinical trial evaluating the safety and efficacy of intravenous umbilical cord blood infusion for the treatment of children with autism spectrum disorder (ASD). We did not target CD34 dosing in this clinical trial because our preclinical studies and early-phase clinical trial data in children with ASD and children with cerebral palsy (CP) did not show any association between improvement and CD34 dosing.Our data showed that the cell responsible for modulation of neuroinflammation, stimulation of oligodendrocyte proliferation, remyelination, and increasing whole brain connectivity is the CD14+ monocyte in cord blood. [1][2][3][4] Cord blood banks do not measure CD14 cell content but do measure total nucleated cells (TNCCs) and CD34. For this reason, selection of cord blood units for the participants with ASD and CP in our clinical trials has been based on TNCC. We are investigating whether infused CD14 cell doses correlate with response but do not have that data at this time.In our first randomized trial using autologous cord blood in young children with CP, we reported an effective dose threshold of 25 million cells/kg. 5 We saw the same trend in our initial phase I trial in children with ASD. 6 Since that time, we have targeted greater TNCC doses in our trials involving children with CP and have observed a dose effect up to 100 million cells/kg (unpublished data). For our trials with children with ASD, we target a minimal dose of 25 million cells/kg. Although CD34 cell dosing is quantitated in all our trials, we have not seen any relationship between CD34 dose and response. The CD34 doses in the trial reported in The Journal are typical of CD34 doses achievable with an unmodified cord blood transplant or cord blood infusion. We are following children in the trial published in The Journal for a period of 12 months postinfusion and will be reporting the 12-month outcome data at a later date.

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Pelizaeus–Merzbacher disease: on the cusp of myelin medicine

Elitt,

Tesar

2024

Trends in Molecular Medicine

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Gene products promoting remyelination are up-regulated in a cell therapy product manufactured from banked human cord blood

Cited by 3 publications

References 53 publications

Human umbilical cord blood monocytes, but not adult blood monocytes, rescue brain cells from hypoxic-ischemic injury: Mechanistic and therapeutic implications

Human umbilical cord blood monocytes, but not adult blood monocytes, rescue brain cells from hypoxic-ischemic injury: Mechanistic and therapeutic implications

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Pelizaeus–Merzbacher disease: on the cusp of myelin medicine

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