Nerve growth factor plays a role in the neurotherapeutic effect of a CD45+ pan-hematopoietic subpopulation derived from human umbilical cord blood in a traumatic brain injury model

Galit Gincberg; Esther Shohami; Victoria Trembovler; Alexander G Alexandrovich; Philip Lazarovici; Uriel Elchalal

doi:10.1016/j.jcyt.2017.11.008

Nerve growth factor plays a role in the neurotherapeutic effect of a CD45⁺ pan-hematopoietic subpopulation derived from human umbilical cord blood in a traumatic brain injury model

Cytotherapy. 2018 Feb;20(2):245-261. doi: 10.1016/j.jcyt.2017.11.008. Epub 2017 Dec 20.

Authors

Galit Gincberg¹, Esther Shohami¹, Victoria Trembovler¹, Alexander G Alexandrovich¹, Philip Lazarovici², Uriel Elchalal³

Affiliations

¹ School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
² School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. Electronic address: philipl@ekmd.huji.ac.il.
³ Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

PMID: 29274773
DOI: 10.1016/j.jcyt.2017.11.008

Abstract

Background aims: Human umbilical cord blood (HUCB) is an important source of stem cells for therapy of hematopoietic disorders and is a potential therapy for various neurological disorders, including traumatic brain injury (TBI). The expression of nerve growth factor (NGF) and its receptors TrkA, p75^NTR and α9β1 integrin on an HUCB CD45⁺ pan-hematopoietic subpopulation was investigated in the context of its neurotherapeutic potential after TBI.

Methods: NGF and its receptors were detected on CD45⁺ cells by reverse transcriptase polymerase chain reaction, flow cytometry analysis and confocal microscopy. CD45⁺ cells were stimulated by TBI brain extracts, and NGF levels were measured by enzyme-linked immunosorbent assay. TBI mice were divided into six groups for xenogeneic intravenous transplantation, 1 day post-trauma, with 1 × 10⁶ CD45⁺ cells untreated or treated with the anti-NGF neutralizing antibody K252a, a TrkA antagonist; VLO5, an α9β1 disintegrin; or negative (vehicle) and positive (NGF) controls.

Results: The HUCB CD45⁺ subpopulation constitutively expresses NGF and its receptors, mainly TrkA and p75^NTR and minor levels of α9β1. In vitro experiments provided evidence that trauma-related mediators from brain extracts of TBI mice induced release of NGF from HUCB CD45⁺ cell cultures. HUCB CD45⁺ cells induced a neurotherapeutic effect in TBI mice, abrogated by cell treatment with either anti-NGF antibody or K252a, but not VLO5.

Conclusions: These findings strengthen the role of NGF and its TrkA receptor in the HUCB CD45⁺ subpopulation's neurotherapeutic effect. The presence of neurotrophin receptors in the HUCB CD45⁺ pan-hematopoietic subpopulation may explain the neuroprotective effect of cord blood in therapy of a variety of neurological disorders.

Keywords: CD45(+) pan-hematopoietic subpopulation; TBI; TrkA receptor; cord blood; nerve growth factor; neuroinflammation; neurotherapeutic effect.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Injuries, Traumatic / pathology
Brain Injuries, Traumatic / therapy*
Chemokine CCL3 / metabolism
Fetal Blood / cytology*
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells / cytology*
Humans
Interleukin-10 / metabolism
Leukocyte Common Antigens / metabolism
Mice, Inbred C57BL
Nerve Growth Factor / genetics
Nerve Growth Factor / metabolism
Nerve Growth Factor / therapeutic use*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Nerve Growth Factor / genetics
Receptors, Nerve Growth Factor / metabolism
Tissue Extracts

Substances

Chemokine CCL3
RNA, Messenger
Receptors, Nerve Growth Factor
Tissue Extracts
Interleukin-10
Nerve Growth Factor
Leukocyte Common Antigens