Pretreatment with Perlecan-Conjugated Laminin-E8 Fragment Enhances Maturation of Grafted Dopaminergic Progenitors in Parkinson’s Disease Model

Author:

Adachi Hiromasa12ORCID,Morizane Asuka13,Torikoshi Sadaharu12,Raudzus Fabian145,Taniguchi Yukimasa6,Miyamoto Susumu3,Sekiguchi Kiyotoshi6,Takahashi Jun12

Affiliation:

1. Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University , Kyoto , Japan

2. Department of Neurosurgery, Kyoto University Graduate School of Medicine , Kyoto , Japan

3. Kobe City Medical Center General Hospital, Center for Clinical Research and Innovation , Hyogo , Japan

4. Neuronal Signaling and Regeneration Unit, Kyoto University Graduate School of Medicine , Kyoto , Japan

5. Medical Education Center/International Education Section, Kyoto University Graduate School of Medicine , Kyoto , Japan

6. Institute for Protein Research, Osaka University , Osaka , Japan

Abstract

Abstract The therapeutic effect of a cell replacement therapy for Parkinson’s disease (PD) depends on the proper maturation of grafted dopaminergic (DA) neurons and their functional innervation in the host brain. In the brain, laminin, an extracellular matrix protein, regulates signaling pathways for the survival and development of neurons by interacting with integrins. The heparan sulfate (HS) chain binds mildly to various neurotrophic factors and regulates their intracellular signaling. Perlecan-conjugated laminin 511/521-E8 fragments (p511/p521) were designed to contain an integrin-binding site and HS chains. Here we examined the effect of treating DA progenitors with p511/p521 prior to transplantation in rodent PD models. In vitro and in vivo experiments showed that p511/p521 treatment enhanced the maturation and neurite extension of the grafted DA progenitors by activating RAS-ERK1/2 signaling. This strategy will contribute to an efficient cell replacement therapy for PD in the future.

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,General Medicine

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