Abstract
BackgroundHuman adipose-derived stem cells (hADSCs) have been proven to be a promising autologous stem cell source for treating various neuronal diseases. Our study indicated that hADSCs could be induced into neuron-like cells in a stepwise manner that are characterized by the positive expression of MAP2, SYNAPSIN 1/2, NF-200, and vGLUT and electrophysiological activity. We first primed hADSCs into neuron-like cells (hADSC-NCs) and then intracerebrally transplanted them into MCAO reperfusion mice to further explore their in vivo survival, migration, integration, fate commitment and involvement in neural circuit rebuilding. ResultsThe hADSC-NCs survived well and transformed into MAP2-positive, Iba1- or GFAP-negative cells in vivo while maintaining some proliferative ability, indicated by positive Ki67 staining after 4 weeks. hADSC-NCs could migrate to almost every brain region, including the cortex, hippocampus, striatum, and hypothalamus, and further differentiate into mature neurons, as confirmed by action potential elicitation and postsynaptic currents. With the aid of a cell suicide system, hADSC-NCs were proven to have functionally integrated into the hippocampal memory circuit, where they contributed to spatial learning and memory rescue, as indicated by LTP improvement and subsequent GCV-induced relapse. In addition to infarction size shrinking and movement improvement, MCAO-reperfused mice showed positive immune modulation, including inhibition of the local proinflammatory factors IL-1α, IL-1β, IL-2, and MIP-1β and enhancement of the anti-inflammatory factors IL-15, IP-10, and MCP-1. ConclusionOverall, hADSC-NCs used as an intermediate autologous cell source for treating stroke can play multiple roles through cell replacement to rebuild neuronal circuits.