Amelioration of ischemic brain injury in rats with human umbilical cord blood stem cells: Mechanisms of action

Laura L. Hocum Stone, Feng Xiao, Jessica Rotschafer, Zhenhong Nan, Mario Juliano, Cyndy D. Sanberg, Paul R. Sanberg, Nicole Kuzmin-Nichols, Andrew Grande, Maxim C J Cheeran, Walter C. Low

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Despite the high prevalence and devastating outcome, there remain a few options for treatment of ischemic stroke. Currently available treatments are limited by a short time window for treatment and marginal efficacy when used. We have tested a human umbilical cord blood-derived stem cell line that has been shown to result in a significant reduction in stroke infarct volume as well as improved functional recovery following stroke in the rat. In the present study we address the mechanism of action and compared the therapeutic efficacy of high- versus low-passage nonhematopoietic umbilical cord blood stem cells (nh-UCBSCs). Using the middle cerebral arterial occlusion (MCAo) model of stroke in Sprague–Dawley rats, we administered nh-UCBSC by intravenous (IV) injection 2 days following stroke induction. These human cells were injected into rats without any immune suppression, and no adverse reactions were detected. Both behavioral and histological analyses have shown that the administration of these cells reduces the infarct volume by 50% as well as improves the functional outcome of these rats following stroke for both high- and low-passaged nh-UCBSCs. Flow cytometry analysis of immune cells present in the brains of normal rats, rats with ischemic brain injury, and ischemic animals with nh-UCBSC treatment confirmed infiltration of macrophages and T cells consequent to ischemia and reduction to normal levels with nh-UCBSC treatment. Flow cytometry also revealed a restoration of normal levels of microglia in the brain following treatment. These data suggest that nh-UCBSCs may act by inhibiting immune cell migration into the brain from the periphery and possibly by inhibition of immune cell activation within the brain. nh-UCBSCs exhibit great potential for treatment of stroke, including the fact that they are associated with an increased therapeutic time window, no known ill-effects, and that they can be expanded to high numbers for, and stored for, treatment.

Original languageEnglish (US)
Pages (from-to)1473-1488
Number of pages16
JournalCell transplantation
Volume25
Issue number8
DOIs
StatePublished - 2016

Bibliographical note

Funding Information:
These studies were funded in part by NIH Grants T32 DA007097, T32 AG029796, R41 NS056626, Suzanne M. Schwarz, and Walter and Ginger Bailey. P.R.S. and W.C.L. are founder and consultant, respectively, of Saneron CCEL Therapeutics, Inc. and are inventors on patents related to cord blood. P.R.S. is the Co-editor-in-chief of Cell Transplantation. Neither P.R.S. nor any member of the editorial office or editorial board affiliated with the authors? institutions was involved with the review process and/or decision making on this manuscript. The remaining authors declare no conflicts of interest.

Keywords

  • Immune response
  • Ischemia
  • Stem cells
  • Stroke

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