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    • Previous MCAO studies of MHP

    2018-11-06

    Previous MCAO studies of MHP36 reverse transcriptase have used rats and assessed functional recovery using behavioural tasks (e.g. neurological severity score, rotational bias, spontaneous activity, bilateral asymmetry test, water maze). Improvement within six weeks after administration has been demonstrated using the bilateral asymmetry test (Modo et al., 2002a), however recovery is incomplete. This is the first study that investigates whether MHP36 cells promote functional recovery after MCAO in mice utilising robust behavioural tests known to assess spontaneous forelimb use (Baskin et al., 2003; Fleming et al., 2004; Schallert et al., 2000; Li et al., 2004; Starkey et al., 2005) and foot faults (Farr et al., 2006; Metz and Whishaw, 2002; Riek-Burchardt et al., 2004). This in the future would allow a more mechanistic insight into how to maximise the function of stem cells by exploiting transgenic mice after stroke.
    Results
    Discussion In a previous study, MHP36 improved functional recovery after transient MCAO, but in that study grafting was done in rats, at 8 distinct contralateral sites and at 2 to 3weeks after MCAO (Veizovic et al., 2001). In addition, MHP36 cells have been tested in mice after 2 vessel global ischaemia and found to reduce ischaemic damage with 50% of cells having neuronal phenotype though no functional recovery was assessed (Wong et al., 2005). We now extend these studies showing success of MHP36 cells after transient MCAO when grafted in mice in 2 ipsilateral sites at 2days after MCAO. The success of MHP36 cells in mice after focal ischaemia in the present study extends the use of these ciNSCs to genetically altered mice for subsequent research into mechanistic insight of these cells after stroke. Improving functional outcome after stroke is the ultimate goal of stroke treatment. Therefore the detection of functional deficits is essential for potential translational applications. Mice due to their small size and quick movements can be perceived as more challenging to handle and train than rats (Wahlsten et al., 2003). Test strategies for mice are hence frequently based on evaluation of simple motor behaviour in standard test batteries (Li et al., 2004; Cook et al., 2002; Lalonde et al., 2003) or neurological score such as Clark\'s deficit score (Clark et al., 1997; De Simoni et al., 2003). While these tests evaluate gross behaviour, they lack resolution when rather specific chronic deficits need to be identified. Clark\'s deficit score has previously shown a significant difference between treatments up till but not beyond 4days post-surgery (De Simoni et al., 2003; Storini et al., 2005). Clark\'s score was not designed in the present study to differentiate between the injection groups given acute time points (3 and 4days post-MCAO), but merely to evaluate if neurological deficit after MCAO was equivalent across groups. Regarding the recovery of sensorimotor deficits, much less has been described in the mouse. In rats and marmosets, tests that have shown successful sensorimotor recovery after MCAO with MHP36 include bilateral asymmetry and amphetamine rotation (Modo et al., 2002a; Veizovic et al., 2001), cognitive function and simple and conditioned discrimination (Virley et al., 1999). Since unilateral brain damage in human and rodents results in deficits of symmetry, we employed a test in mice that detects asymmetries, namely the cylinder test. The advantage of the cylinder test is that it can detect even mild neurological impairments (Hua et al., 2002) and factors out confounding variables such as overall decrease in activity after surgical induction of stroke as additional trials can be performed. This is the first time the cylinder test has been used to assess the potential of MHP36 cells. We observed symmetrical use of both paws in sham animals and a marked preference for use of the non-impaired (ipsilateral) paw after MCAO. Importantly, treatment with MHP36 reduced this asymmetry [by >70%]. Therefore, we have introduced a mouse model in behavioural assay to better study potential functional effects of stem cells, enabling future studies on potential functional effects in mouse mutants that target particular signalling/developmental pathways for dissecting molecular mechanisms of stem cells. Neuronal connections are continuously remodelled and suffer intense adaptive functional and structural reorganisation after lesions (Carmichael, 2003; Giraldi-Guimaraes et al., 2009; Rossi et al., 2007). This restorative reorganisation is one of the most important mechanisms underlying functional recovery as described below.