Umbilical Cord Mesenchymal Stem Cells Derived Neurospheres Promote Long-term functional recovery But Aggravate Acute Phase Inflammation in Experimental Stroke

Abstract

Human umbilical cord mesenchymal stem cells (UC-MSCs) transplantation has been shown to ameliorate intracerebral hemorrhage (ICH) in animal and clinical studies. We previously reported an easy one-step method to induce UC-MSCs into neurospheres with much enhanced neurogenic and angiogenic potential. In the present study, we further evaluated the neuro-protective effects of these UC-MSCs derived neurospheres (UC-MSCs-NS) using a murine collagenase induced ICH model. We compared the effects of UC-MSCs or UC-MSCs-NS transplantation at two different time-points: 3 h after ICH induction (early transplantation) or three days after ICH induction (delayed transplantation). The results showed that UC-MSCs exhibited favorable effects at both time-points whereas UC-MSCs-NS early delivery led to increased cell apoptosis, exacerbated brain edema, enlarged ICH volume and deteriorated neurological function. In vivo inflammatory cytokine analysis indicated UC-MSCs transplantation was able to attenuate the acute phase secretion of inflammatory cytokines TNF-α and IL-1β whereas UC-MSCs-NS immediate transplantation led to increased levels of these cytokines. However, long-term follow-up experiment showed delayed UC-MSCs-NS transplantation was superior to UC-MSCs transplantation alone in terms of increased neurogenic reconstitution. Our results suggest both UC-MSCs and UC-MSCs-NS can exert favorable effects in ICH therapy but the infusion of UC-MSCs-NS should avoid the super-early phase of ICH. We believe UC-MSCs derived neurospheres should be further exploited for chronic refractory neurological disorders such as chronic phase of stroke and various neurodegenerative disorders such as Alzheimer’s disease.