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Stroke Induces Mesenchymal Stem Cell Migration to Infarcted Brain Areas Via CXCR4 and C-Met Signaling

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Abstract

Mesenchymal stem cells circulate between organs to repair and maintain tissues. Mesenchymal stem cells cultured with fetal bovine serum have therapeutic effects when intravenously administered after stroke. However, only a small number of mesenchymal stem cells reach the brain. We hypothesized that the serum from stroke patients increases mesenchymal stem cells trophism toward the infarcted brain area. Mesenchymal stem cells were grown in fetal bovine serum, normal serum from normal rats, or stroke serum from ischemic stroke rats. Compared to the fetal bovine serum group, the stroke serum group but not the normal serum group showed significantly greater migration toward the infarcted brain area in the in vitro and in vivo models (p < 0.05). Both C-X-C chemokine receptor type 4 and c-Met expression levels significantly increased in the stroke serum group than the others. The enhanced mesenchymal stem cells migration of the stroke serum group was abolished by inhibition of signaling. Serum levels of chemokines, cytokines, matrix metalloproteinase, and growth factors were higher in stroke serum than in normal serum. Behavioral tests showed a significant improvement in the recovery after stroke in the stroke serum group than the others. Stroke induces mesenchymal stem cells migration to the infarcted brain area via C-X-C chemokine receptor type 4 and c-Met signaling. Culture expansion using the serum from stroke patients could constitute a novel preconditioning method to enhance the therapeutic efficiency of mesenchymal stem cells.

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Acknowledgements

This study was supported by a grant from the Korea Health Technology R&D Project, the Ministry of Health & Welfare (HI14C1624).

STem cell Application Researches and Trials In NeuroloGy (STARTING)-2 collaborators: Oh Young Bang, MD, PhD; Ji Hyun Lee; Gyeong Joon Moon, PhD; Yeon Hee Cho, MS; Ji Hee Sung; Soo Yoon Kim, MS; Jeong Pyo Son, MS; Dong Hee Kim, MS; Jong-Won Chung, MD; Mi Ji Lee, MD; Suk Jae Kim, MD; Soo Kyoung Kim, MD; Yoon Mi Kang, MS; Yong Man Kim, PhD; Hyun Soo Kim, MD, PhD; Jun Ho Jang, MD, PhD; Won Hyuk Chang, MD, PhD; Yun-Hee Kim, MD, PhD.

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Authors and Affiliations

  1. Departments of Neurology, Samsung Medical Center, Sungkyunkwan University, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, South Korea

    Oh Young Bang

  2. Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea

    Oh Young Bang, Dong Hee Kim, Ji Hyun Lee & Jeong Pyo Son

  3. Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center, Seoul, South Korea

    Oh Young Bang, Gyeong Joon Moon, Dong Hee Kim, Ji Hyun Lee, Sooyoon Kim, Jeong Pyo Son & Yeon Hee Cho

  4. Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, South Korea

    Gyeong Joon Moon

  5. Department of Physical and Rehabilitation Medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea

    Won Hyuk Chang & Yun-Hee Kim

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  1. Oh Young Bang
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  2. Gyeong Joon Moon
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Consortia

the STARTING-2 trial investigators

  • Oh Young Bang
  • , Ji Hyun Lee
  • , Gyeong Joon Moon
  • , Yeon Hee Cho
  • , Ji Hee Sung
  • , Soo Yoon Kim
  • , Jeong Pyo Son
  • , Dong Hee Kim
  • , Jong-Won Chung
  • , Mi Ji Lee
  • , Suk Jae Kim
  • , Soo Kyoung Kim
  • , Yoon Mi Kang
  • , Yong Man Kim
  • , Hyun Soo Kim
  • , Jun Ho Jang
  • , Won Hyuk Chang
  •  & Yun-Hee Kim

Contributions

O.Y.B.: conception and design, manuscript writing, financial support, collection and/or assembly of data, data analysis and interpretation, administrative support, final approval of manuscript; D.H.K.: provision of study material, collection and/or assembly of data, data analysis and interpretation; J.H.L.: collection and/or assembly of data, data analysis and interpretation, provision of study material; S.Y.K.: collection and/or assembly of data, data analysis and interpretation, provision of study material; J.P.S.: collection and/or assembly of data, data analysis and interpretation, provision of study material; Y.H.C.: collection and/or assembly of data, data analysis and interpretation, provision of study material; J.M.C.: collection and/or assembly of data, provision of study material; W.H.C.: provision of study material or patients, administrative support; Y.H.K.: provision of study material or patients, administrative support; G.J.M: conception and design, collection and/or assembly of data, data analysis and interpretation, final approval of manuscript.

Corresponding author

Correspondence to Oh Young Bang.

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Conflict of Interest

The authors have no conflicts of interest to report.

Funding

This study was supported by a grant from the Korea Health Technology R&D Project, the Ministry of Health & Welfare (HI14C1624).

Ethical Approval

In this study, all human subject research was approved by the local institutional review board (Samsung Medical Center Institutional Review Board, Approval No. SMC 2011-10-047-047). All patients or guardians of patients provided written informed consent to participate in this study. All animal experiments were approved by Institutional Animal Care and Use Committee (IACUC) of Samsung Biomedical Research Institute (SBRI, Approval No. 201300117002) and performed under the Institute of Laboratory Animal Resources (ILAR) guidelines. All animals were maintained in compliance with the relevant laws and institutional guidelines of Laboratory Animal Research Center (LARC; AAALAC International approved facility, No. 001003) at the Samsung Medical Center.

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Bang, O.Y., Moon, G.J., Kim, D.H. et al. Stroke Induces Mesenchymal Stem Cell Migration to Infarcted Brain Areas Via CXCR4 and C-Met Signaling. Transl. Stroke Res. 8, 449–460 (2017). https://doi.org/10.1007/s12975-017-0538-2

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  • DOI: https://doi.org/10.1007/s12975-017-0538-2

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