Ephrin-B2 PB-mononuclear cells reduce early post-stroke deficit in diabetic mice but not long-term memory impairment

Adrien Cogo; Gabrielle Mangin; Sarah Mouazan; Tatiana Merkulova-Rainon; Jean-Pierre Riveline; Jean-François Gautier; Mathilde Varret; Nathalie Kubis

doi:10.1016/j.expneurol.2021.113864

Ephrin-B2 PB-mononuclear cells reduce early post-stroke deficit in diabetic mice but not long-term memory impairment

Exp Neurol. 2021 Dec:346:113864. doi: 10.1016/j.expneurol.2021.113864. Epub 2021 Sep 11.

Authors

Adrien Cogo¹, Gabrielle Mangin¹, Sarah Mouazan¹, Tatiana Merkulova-Rainon², Jean-Pierre Riveline³, Jean-François Gautier³, Mathilde Varret¹, Nathalie Kubis⁴

Affiliations

¹ Université de Paris, INSERM U1148, Laboratory for Vascular Translational Science, F-75018 Paris, France.
² Institut Vaisseaux Sang, Hôpital Lariboisière, 75475 Paris, France.
³ Department of Diabetology and Endocrinology, Lariboisière Hospital, AP-HP, 2 rue Ambroise Paré, 75010 Paris, France; Unité INSERM U1138 Immunity and Metabolism in Diabetes, ImMeDiab Team, Centre de Recherches des Cordeliers, Paris, France, Université de Paris, Paris, France.
⁴ Université de Paris, INSERM U1148, Laboratory for Vascular Translational Science, F-75018 Paris, France; Service de Physiologie Clinique, AP-HP, Hôpital Lariboisière, 75475 Paris, France. Electronic address: nathalie.kubis@aphp.fr.

PMID: 34520725
DOI: 10.1016/j.expneurol.2021.113864

Abstract

Background and purpose: Post-stroke cognitive impairment (PSCI) has become a major public health issue, as a leading cause of dementia. The inflammation that develops soon after cerebral artery occlusion and may persist for weeks or months after stroke is a key component of PSCI. Our aim was to take advantage of the immunomodulatory properties of peripheral blood mononuclear cells (PB-MNC) stimulated with ephrin-B2/fc (PB-MNC⁺) for preventing PSCI.

Methods: Cortical infarct was induced by thermocoagulation of the middle cerebral artery in male diabetic mice (streptozotocin IP). PB-MNC were isolated from diabetic human donors, washed with recombinant ephrin-B2/Fc and injected into the mice intravenously on the following day. Infarct volume, sensorimotor deficit, cell death and immune cell densities were assessed on day 3. Six weeks later, cognitive assessment was performed using the Barnes maze.

Results: PB-MNC⁺ transplanted in post-stroke diabetic mice reduced the neurological deficit, infarct volume and apoptosis at D3, without modification of microglial cells, astrocytes and T-lymphocytes densities in the brain. Barnes maze assessment of memory showed that the learning, retention and reversal phases were not significantly modified by cell therapy.

Conclusions: Intravenous PB-MNC⁺ administration the day after stroke induction in diabetic mice improved sensorimotor deficit and reduced infarct volume at the short term, but was unable to prevent long-term memory loss. To what extent diabetes impacts on cell therapy efficacy will have to be specifically investigated in the future. Including vascular risk factors systematically in preclinical studies of cell therapy will provide a comprehensive understanding of the mechanisms potentially limiting cell efficacy and also to identify good and bad responders, particularly in the long term.

Keywords: Cell therapy; Cell transplantation; Cerebral ischemia; Diabetes; Stroke.

Publication types

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

MeSH terms

Administration, Intravenous
Animals
Cell- and Tissue-Based Therapy / methods*
Diabetes Mellitus, Experimental / physiopathology
Diabetes Mellitus, Experimental / psychology
Diabetes Mellitus, Experimental / therapy*
Ephrin-B2 / administration & dosage*
Leukocytes, Mononuclear / transplantation*
Male
Memory Disorders / physiopathology
Memory Disorders / psychology
Memory Disorders / therapy*
Mice
Mice, Inbred C57BL
Stroke / physiopathology
Stroke / psychology
Stroke / therapy*

Substances

Ephrin-B2