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Translating G-CSF as an Adjunct Therapy to Stem Cell Transplantation for Stroke

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Abstract

Among recently investigated stroke therapies, stem cell treatment holds great promise by virtue of their putative ability to replace lost cells, promote endogenous neurogenesis, and produce behavioral and functional improvement through their “bystander effects.” Translating stem cell in the clinic, however, presents a number of technical difficulties. A strategy suggested to enhance therapeutic utility of stem cells is combination therapy, i.e., co-transplantation of stem cells or adjunct treatment with pharmacological agents and substrates, which is assumed to produce more profound therapeutic benefits by circumventing limitations of individual treatments and facilitating complementary brain repair processes. We previously demonstrated enhanced functional effects of co-treatment with granulocyte-colony stimulating factor (G-CSF) and human umbilical cord blood cell (hUCB) transplantation in animal models of traumatic brain injury (TBI). Here, we suggest that the aforementioned combination therapy may also produce synergistic effects in stroke. Accordingly, G-CSF treatment may reduce expression of pro-inflammatory cytokines and enhance neurogenesis rendering a receptive microenvironment for hUCB engraftment. Adjunct treatment of G-CSF with hUCB may facilitate stemness maintenance and guide neural lineage commitment of hUCB cells. Moreover, regenerative mechanisms afforded by G-CSF-mobilized endogenous stem cells, secretion of growth factors by hUCB grafts and G-CSF-recruited endothelial progenitor cells (EPCs), as well as the potential graft–host integration that may promote synaptic circuitry re-establishment could altogether produce more pronounced functional improvement in stroked rats subjected to a combination G-CSF treatment and hUCB transplantation. Nevertheless, differences in pathology and repair processes underlying TBI and stroke deserve consideration when testing the effects of combinatorial G-CSF and hUCB cell transplantation for stroke treatment. Further studies are also required to determine the safety and efficacy of this intervention in both preclinical and clinical stroke studies.

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Acknowledgments

This research was funded by the National Institutes of Health National Institute of Neurological Disorders and Stroke 1R01NS071956-01A1, 1R21NS089851-0, James and Esther King Biomedical Research Foundation 1KG01-33966, and Loma Linda University School of Pharmacy. The authors thank Mia Borlongan for help with drawing of the figure.

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  1. Department of Pharmaceutical and Administrative Sciences, Loma Linda University, Loma Linda, CA, 92350, USA

    Ike dela Peña

  2. Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, 33612, USA

    Cesar V. Borlongan

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  1. Ike dela Peña
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Correspondence to Ike dela Peña.

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This article does not contain studies with human participants or animals performed by any of the authors.

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This study was supported, in part, by the National Institutes of Health National Institute of Neurological Disorders and Stroke 1R01NS071956-01A1, 1R21NS089851-01, James and Esther King Biomedical Research Foundation 1KG01-33966, and Loma Linda University School of Pharmacy.

Conflict of Interest

C. V. Borlongan has patents and patent applications on stem cell therapy. I. dela Peña declares that he has no conflict of interest.

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dela Peña, I., Borlongan, C.V. Translating G-CSF as an Adjunct Therapy to Stem Cell Transplantation for Stroke. Transl. Stroke Res. 6, 421–429 (2015). https://doi.org/10.1007/s12975-015-0430-x

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  • DOI: https://doi.org/10.1007/s12975-015-0430-x

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