Therapeutic time window of multipotent adult progenitor therapy after traumatic brain injury

Bedi, Supinder S.; Aertker, Benjamin M.; Liao, George P.; Caplan, Henry W.; Bhattarai, Deepa; Mandy, Fanni; Mandy, Franciska; Fernández, Luis G.; Zelnick, Pamela; Mitchell, Matthew B.; Schiffer, Walter; Johnson, Martin L.; Denson, Emma; Prabhakara, Karthik S.; Xue, Hasen; Smith, Philippa; Uray, Karen; Olson, Scott D.; Mays, Robert W.; Cox, Charles S.

doi:10.1186/s12974-018-1122-8

Cited by 34 publications

(36 citation statements)

References 47 publications

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“…These data indicate that TSPO is a good marker to target in order to observe increases of pro-in ammatory microglia in vivo. Ex vivo, we have previously utilized morphology to delineate between activated and resting microglia after TBI [10][11][12]22]. Microglia are activated after a CNS injury.…”

Section: Discussionmentioning

confidence: 99%

“…Microglia are activated after a CNS injury. They retract their processes and adopt an amoeboid morphology [2,7,[9][10][11][12]. Microglia are responsible for clearance of dead cells and other debris, such as dead axons and myelin and, therefore, have a neuroprotective role [23], however, chronic activation of microglia can negatively affect neuronal function and hippocampal dependent behavior [10,24,25].…”

Section: Discussionmentioning

confidence: 99%

“…005-000-121; Jackson Immunoresearch Laboratories, West Grove, PA) in PBST. The last step of day one involved incubating the brain slices with the primary antibody IBA-1, which is used to identify microglia/macrophage morphology (rabbit polyclonal primary antibody, 1:500; Wako Chemicals USA, Cat# 019-19741, RRID: AB_2313566) [10][11][12][13]19] The primary antibody was prepared in PBTB (PBST, 2% bovine serum albumin [A9647; Sigma-Aldrich] and 1% goat serum), and sections were incubated overnight at 4 o C. The following day, sections were washed with PBST and incubated with a goat anti-rabbit IgG secondary antibody (1:500; red/568; Molecular Probes (Invitrogen) Cat# A11011, RRID: AB143157) in PBTB for 2 hours at room temperature. The sections were again rinsed four times with PBST, mounted on slides, and cover-slipped with Fluoromount-G (SouthernBiotech) for analysis.…”

Section: Tissue Harvest and Immunohistochemistrymentioning

confidence: 99%

“…We marked several microglia as landmarks while moving to the adjacent photomicrograph to prevent "double-counting". IBA-1 labeled cells were further quanti ed based on the following microglia morphologies: rami ed or amoeboid as previously described (Torres-Platas et al, 2014), (Zhang et al, 2008), (Bedi et al, , 2018.…”

Section: Microglia Morphology Quanti Cationmentioning

confidence: 99%

“…After TBI, microglia are activated and undergo considerable remodeling. They retract their processes and typically adopt an amoeboid morphology [2,7,[9][10][11][12][13]. Once activated, microglia can polarize towards a pro-in ammatory phenotype which can result in chronic neuroin ammation, oxidative stress and neuronal dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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PET Imaging of Peripheral Benzodiazepine Receptor Standard Uptake Value Increases After Controlled Cortical Impact, a Rodent Model of Traumatic Brain Injury.

Aertker

Kumar

Caplan

et al. 2020

Preprint

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Background: Traumatic brain injury (TBI) disrupts the complex arrangement of neuronal and glial cells. As a result of TBI there is activation of microglia. Activated microglia after injury can be measured in vivo by using positron emission topography (PET) ligand peripheral benzodiazepine receptor (PBR28) and their phenotypes (activated vs resting) can be assessed (ex vivo) using morphology. This study aims to utilize in vivo (PET) and ex vivo (morphology) to assess the changes in microglia after a controlled cortical impact (CCI), a rodent model for TBI.Methods: Male Sprague Dawley rats underwent a sham injury or severe CCI. Microglia activation was assessed 120 hours after the injury by PET/CT imaging using the radioligand [11C] PBR-28. Standardized uptake values (PBR28suv) were calculated over the duration of the scan and mean values were compared. In order to verify in vivo results, ex vivo morphological analysis [ramified (resting) or amoeboid-shaped (activated)] was performed (dentate gyrus, corpus callosum and thalamus) with the antibody IBA-1. To further conclude that PBR is a marker for activated microglia after CCI, we examined co-staining of PBR with microglia and astrocytes.Results: In vivo and ex vivo results were complementary. Injured animals displayed greater PBR28suv when compared to sham animals. Immunohistochemistry demonstrated elevated numbers of activated microglia in the ipsilateral dentate gyrus, corpus callosum and thalami of injured animals compared to sham animals. Additionally, PBR co-stained with microglia and not astrocytes.Conclusion: CCI, a rodent model of TBI resulted in a significant increase in PBR28suv due to injury. Similarly, morphological analysis demonstrated a significant increase in amoeboid-shaped (activated) microglia. These results serve as a surrogate marker for increased neuroinflammation in the brains of severely injured animals. PBR28suv can serve as an in vivo tracking system for monitoring neuroinflammation following TBI and cellular therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Tissue Harvest and Immunohistochemistrymentioning

confidence: 99%

Section: Microglia Morphology Quanti Cationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PET Imaging of Peripheral Benzodiazepine Receptor Standard Uptake Value Increases After Controlled Cortical Impact, a Rodent Model of Traumatic Brain Injury.

Aertker

Kumar

Caplan

et al. 2020

Preprint

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Pre‐injury monocyte/macrophage depletion results in increased blood–brain barrier permeability after traumatic brain injury

Aertker¹,

Kumar²,

Prabhakara³

et al. 2019

J of Neuroscience Research

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Traumatic brain injury (TBI) effects both the brain and the immune system. Circulating monocytes/macrophages (Mo/Ma) after a TBI may play an important role in preserving the blood–brain barrier (BBB), reducing brain edema, and interacting with resident microglia. To elucidate the role of circulating Mo/Ma, we utilized a monocyte/macrophage depletion model in response to TBI in male rats. Clodronate liposomes (CL) were used to deplete circulating Mo/Ma. A controlled cortical impact (CCI) injury model was used to create a TBI. All animals received either CL or PBS liposomes (PL), 48 and 24 hr prior to the procedure, and were sacrificed 72 hr post‐injury for analysis of BBB permeability, brain edema, whole blood (Mo/Ma and granulocytes), and/or microglial analysis. Animals undergoing Mo/Ma depletion with CL prior to CCI (CCI‐CL) were found to have increased BBB permeability when compared to non‐depleted CCI (CCI‐PL) animals. At 72 hr following injury, Sham‐CL maintained on average an 82% reduction in the whole blood monocytes when compared to Sham‐PL (p < 0.001). Monocytes in the whole blood remained significantly lower in CCI‐CL animals when compared to CCI‐PL (p < 0.001). The number of granulocytes in the whole blood of CCI‐CL animals was higher at 3 days when compared to CCI‐PL (p < 0.022). Surprisingly, the depletion of Mo/Ma did not affect brain edema. However, the depletion of Mo/Ma did result in a significant decrease in microglia (CCI‐CL vs. CCI‐PL, p < 0.012). In conclusion, an intact Mo/Ma population is required to repair BBB integrity and microglial response following injury.

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Human cord blood-derived regulatory T-cell therapy modulates the central and peripheral immune response after traumatic brain injury

Caplan

Prabhakara

Kumar

et al. 2020

Stem Cells Translational Medicine

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Traumatic brain injury (TBI) causes a profound inflammatory response within the central nervous system and peripheral immune system, which contributes to secondary brain injury and further morbidity and mortality. Preclinical investigations have demonstrated that treatments that downregulate microglia activation and polarize them toward a reparative/anti‐inflammatory phenotype have improved outcomes in preclinical models. However, no therapy to date has translated into proven benefits in human patients. Regulatory T cells (Treg) have been shown to downregulate pathologic immune responses of the innate and adaptive immune system across a variety of pathologies. Furthermore, cellular therapy has been shown to augment host Treg responses in preclinical models; yet, studies investigating the use of Treg as a therapeutic for TBI are lacking. In a rodent TBI model, we demonstrate that human umbilical cord blood Treg modulate the central and peripheral immune response after injury in vitro and in vivo.

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Therapeutic time window of multipotent adult progenitor therapy after traumatic brain injury

Cited by 34 publications

References 47 publications

PET Imaging of Peripheral Benzodiazepine Receptor Standard Uptake Value Increases After Controlled Cortical Impact, a Rodent Model of Traumatic Brain Injury.

PET Imaging of Peripheral Benzodiazepine Receptor Standard Uptake Value Increases After Controlled Cortical Impact, a Rodent Model of Traumatic Brain Injury.

Pre‐injury monocyte/macrophage depletion results in increased blood–brain barrier permeability after traumatic brain injury

Human cord blood-derived regulatory T-cell therapy modulates the central and peripheral immune response after traumatic brain injury

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