Strength and fine dexterity recovery profiles after a primary motor cortex insult and effect of a neuronal cell graft.

Abstract

The aim of this study was to set up (a) a large primary motor cortex (M1) lesion in rodent and (b) the conditions for evaluating a long-lasting motor deficit in order to propose a valid model to test neuronal replacement therapies aimed at improving motor deficit recovery. A mitochondrial toxin, malonate, was injected to induce extensive destruction of the forelimb M1 cortex. Three key motor functions that are usually evaluated following cerebral lesion in the clinic-strength, target reaching, and fine dexterity-were assessed in rats by 2 tests, a forelimb grip strength test and a skilled reaching task (staircase) for reaching and dexterity. The potential enhancement of postlesion recovery induced by a neuronal cell transplantation was then explored and confirmed by histological analyses. Both tests showed a severe functional impairment 2 days post lesion, however, reaching remained intact. Deficits in forelimb strength were long lasting (up to 3 months) but spontaneously recovered despite the extensive lesion size. This natural grip strength recovery could be enhanced by cell therapy. Histological analyses confirmed the presence of grafted cells 3 months postgraft and showed partial tissue reconstruction with some living neuronal cells in the graft. In contrast, fine dexterity never recovered in the staircase test even after grafting. These results suggest that cell replacement was only partially effective and that the forelimb M1 area may be a node of the sensorimotor network, where compensation from secondary pathways could account for strength recovery but recovery of forelimb fine dexterity requires extensive tissue reconstruction.

Wet spinning and radial self-assembly of a carbohydrate low molecular weight gelator into well organized hydrogel filaments

“…25 Still in the context of neuronal cell culture, it has been shown that oriented scaffolds are able to guide the development of neurites and axons in one preferential direction and can help in a suitable tissue reconstruction. [26][27][28] Thus, for the scaffolding purpose, and also more generally for extending the scope of LMWG applications, our objective was to explore how fluidics (or microfluidics) can drive the self-assembly of the gelator into well-defined structures and shapes.…”

Regenerative potential of primary adult human neural stem cells on micropatterned bio-implants boosts motor recovery

“…Cortical lesions focused on the caudal forelimb motor area (M1) were induced by malonate injection (5 μl, 3M solution, pH 7.4 in PBS; Sigma-Aldrich, France) ( n = 53) or PBS for the sham group ( n = 8) [ 27 ] at the following stereotaxic coordinates: 2.5 mm lateral to Bregma, and 2 mm deep. Only animals that displayed substantial neurological dysfunctions (grip strength < 60% of pre-lesion value, n = 46 out of 53 lesioned rats) 1 week after injury were selected (Fig.…”

“…Another group of lesioned animals each received five implants without any cells (Implants Alone group, n = 6), and another group underwent the same surgery but the implants were immediately removed (Sham Implants group, n = 10). The final group of lesioned rats received a cell graft of 5 × 10 5 hNSCs, by perfusion of 5 μl of cell suspension at 1 μl/min (hNSCs group, n = 6), as already described elsewhere [ 27 ].…”

“…Before the study, the animals were acclimatized and trained on a controlled diet for the behavioural tests, as already described [ 27 ]. Behavioural testing to detect motor deficits was performed 1 week before lesion (baseline), then 48 h post lesion, 24 h post graft and once a month for 3 months after the insult.…”

“…Biomaterials have been developed to locally deliver pharmacological growth factors such as vascular endothelial growth factor (VEGF) [ 15 ] and brain-derived neurotrophic factor (BDNF) [ 25 ] to favour tissue reconstruction. Another approach consists of seeding cells, be they adult rat neural progenitor cells [ 26 ], human MSCs [ 22 ] or hNT2, a human neuronal cell line [ 27 ], on the scaffold before implantation, to enhance the potential effect of both grafted cells and biomaterials [ 27 ]. The challenge is still to find both a biomaterial adapted to neuronal differentiation and cell sources able to regenerate adult human brain in order to restore sensorimotor functions.…”