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Wnt- and glutamate-receptors orchestrate stem cell dynamics and asymmetric cell division.

ABSTRACT: The Wnt-pathway is part of a signalling network that regulates many aspects of cell biology. Recently, we discovered crosstalk between AMPA/Kainate-type ionotropic glutamate receptors (iGluRs) and the Wnt-pathway during the initial Wnt3a-interaction at the cytonemes of mouse embryonic stem cells (ESCs). Here, we demonstrate that this crosstalk persists throughout the Wnt3a-response in ESCs. Both AMPA and Kainate receptors regulate early Wnt3a-recruitment, dynamics on the cell membrane, and orientation of the spindle towards a Wnt3a-source at mitosis. AMPA receptors specifically are required for segregating cell fate components during Wnt3a-mediated asymmetric cell division (ACD). Using Wnt-pathway component knockout lines, we determine that Wnt co-receptor Lrp6 has particular functionality over Lrp5 in cytoneme formation, and in facilitating ACD. Both Lrp5 and 6, alongside pathway effector β-catenin act in concert to mediate the positioning of the dynamic interaction with, and spindle orientation to, a localised Wnt3a-source. Wnt-iGluR crosstalk may prove pervasive throughout embryonic and adult stem cell signalling.

SUBMITTER: Junyent S

PROVIDER: S-EPMC8177892 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Wnt- and glutamate-receptors orchestrate stem cell dynamics and asymmetric cell division.

Junyent Sergi S Reeves Joshua C JC Szczerkowski James LA J Garcin Clare L CL Trieu Tung-Jui TJ Wilson Matthew M Lundie-Brown Jethro J Habib Shukry J SJ

eLife 20210524

The Wnt-pathway is part of a signalling network that regulates many aspects of cell biology. Recently, we discovered crosstalk between AMPA/Kainate-type ionotropic glutamate receptors (iGluRs) and the Wnt-pathway during the initial Wnt3a-interaction at the cytonemes of mouse embryonic stem cells (ESCs). Here, we demonstrate that this crosstalk persists throughout the Wnt3a-response in ESCs. Both AMPA and Kainate receptors regulate early Wnt3a-recruitment, dynamics on the cell membrane, and orien ...[more]

PMID: 34028355

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Project description:The regeneration of osteoporotic bone defects remains challenging as the critical stem cell function is impaired by inflammatory microenvironment. Synthetic materials that intrinsically direct osteo-differentiation versus self-renewal of recruited stem cell represent a promising alternative strategy for endogenous bone formation. Therefore, a microenvironmentally optimized polyurethane (PU) /n-HA scaffold to enable sustained delivery of gastrodin is engineered to study its effect on the osteogenic fate of stem cells. It exhibited interconnected porous networks and an elevated sequential gastrodin release pattern to match immune-osteo cascade concurrent with progressive degradation of materials. In a critical-sized femur defect model of osteoporotic rat, 5% gastrodin-PU/n-HA potently promoted neo-bone regeneration by facilitating M2 macrophage polarization and CD146+ host stem cell recruitment to defective site. The implantation time-dependently increased the bone marrow mesenchymal stem cell (BMSC) population, and further culture of BMSCs showed a robust ability of proliferation, migration, and mitochondrial resurgence. Of note, some of cell pairs produced one stemness daughter cell while the other committed to osteogenic lineage in an asymmetric cell division (ACD) manner, and a much more compelling ACD response was triggered when 5% gastrodin-PU/n-HA implanted. Further investigation revealed that one-sided concentrated presentation of aPKC and β-catenin in dividing cells effectively induced asymmetric distribution, which polarized aPKC biased the response of the daughter cells to Wnt signal. The asymmetric cell division in skeletal stem cells (SSCs) was mechanically comparable to BMSCs and also governed by distinct aPKC and β-catenin biases. Concomitantly, delayed bone loss adjacent to the implant partly alleviated development of osteoporosis. In conclusion, our findings provide insight into the regulation of macrophage polarization combined with osteogenic commitment of recruited stem cells in an ACD manner, advancing scaffold design strategy for endogenous bone regeneration.

Dataset Information

Wnt- and glutamate-receptors orchestrate stem cell dynamics and asymmetric cell division.

Publications

Wnt- and glutamate-receptors orchestrate stem cell dynamics and asymmetric cell division.

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