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Evidence for a retinal progenitor cell in the postnatal and adult mouse.

ABSTRACT: Progress in cell therapy for retinal disorders has been challenging. Recognized retinal progenitors are a heterogeneous population of cells that lack surface markers for the isolation of live cells for clinical implementation. In the present application, our objective was to use the stem cell factor receptor c-Kit (CD117), a surface marker, to isolate and evaluate a distinct progenitor cell population from retinas of postnatal and adult mice. Here we report that, by combining traditional methods with fate mapping, we have identified a c-Kit-positive (c-Kit+) retinal progenitor cell (RPC) that is self-renewing and clonogenic in vitro, and capable of generating many cell types in vitro and in vivo. Based on cell lineage tracing, significant subpopulations of photoreceptors in the outer nuclear layer and bipolar, horizontal, amacrine and Müller cells in the inner nuclear layer are the progeny of c-Kit+ cells in vivo. The RPC progeny contributes to retinal neurons and glial cells, which are responsible for the conversion of light into visual signals. The ability to isolate and expand in vitro live c-Kit+ RPCs makes them a future therapeutic option for retinal diseases.

SUBMITTER: Chen X

PROVIDER: S-EPMC6450801 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Evidence for a retinal progenitor cell in the postnatal and adult mouse.

Chen Xi X Wang Shaojun S Xu Haiwei H Pereira Joao D JD Hatzistergos Konstantinos E KE Saur Dieter D Seidler Barbara B Hare Joshua M JM Perrella Mark A MA Yin Zheng Qin ZQ Liu Xiaoli X

Stem cell research 20170624

Progress in cell therapy for retinal disorders has been challenging. Recognized retinal progenitors are a heterogeneous population of cells that lack surface markers for the isolation of live cells for clinical implementation. In the present application, our objective was to use the stem cell factor receptor c-Kit (CD117), a surface marker, to isolate and evaluate a distinct progenitor cell population from retinas of postnatal and adult mice. Here we report that, by combining traditional methods ...[more]

PMID: 28672156

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Project description:BACKGROUND:Millions of people are affected with retinal diseases that eventually cause blindness, and retinal progenitor cell (RPC) transplantation is a promising therapeutic avenue. However, RPC expansion and the underlying regulation mechanisms remain elusive. METHODS:Adult mouse neural RPCs (mNRPCs) were isolated and amplified with the combination of basic fibroblast growth factor (bFGF) and glycogen synthase kinase 3 (GSK3) inhibitor CHIR99021. The progenitor characteristics were evaluated with RT-PCR, immunocytochemistry (ICC), western blot, flow cytometry, and transcriptome analysis prior to transplantation. By treating cells with or without bFGF and CHIR99021 at different time points, the mechanism for mNRPCs' self-renewal was investigated by transcriptome analysis and western blot assay. RESULTS:mNRPCs were self-renewing in the presence of bFGF and CHIR99021 and showed prominent RPC characteristics. bFGF was essential in promoting cell cycle by facilitating G1/S and G2/M transitions. bFGF combined with CHIR99021 activated the non-canonical Wnt5A/Ca2+ pathway and form a calcium homeostasis. In addition, the self-renewing mNRPCs could differentiate into rod photoreceptor-like cells and retinal pigment epithelium (RPE)-like cells by in vitro induction. When green fluorescent protein (GFP)-labeled cells were transplanted into the subretinal space (SRS) of Pde6b (rd1) mice (also known as RD1 mice, or rodless mice), the cells survived for more than 12 weeks and migrated into the retina. Parts of the recipient retina showed positive expression of photoreceptor marker rhodopsin. Transplanted cells can migrate into the retina, mainly into the inner cell layer (INL) and ganglion cell layer (GCL). Some cells can differentiate into astrocytes and amacrine cells. Cultured mNRPCs did not form tumors after transplanted into NOD/SCID mice for 6 months. CONCLUSIONS:Present study developed an approach to maintain long-term self-renewal of RPCs from adult retinal tissues and revealed that activation of the non-canonical Wnt5A/Ca2+ pathway may participate in regulating RPC self-renewal in vitro. This study presents a very promising platform to expand RPCs for future therapeutic application.

Dataset Information

Evidence for a retinal progenitor cell in the postnatal and adult mouse.

Publications

Evidence for a retinal progenitor cell in the postnatal and adult mouse.

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