RB1-Fc selectively inhibits the activity of the heparan-sulfate proteoglycan hGPC4. The nanobody-Fc fusion RB1-Fc binds native hGPC4 on the cell surface and blocks its function. Selective inhibition of hGPC4 enables the dissection of its roles in cell signaling, cell behavior, and fate decisions, and provides opportunities for controlled differentiation in tissue engineering and regenerative medicine.
Human induced pluripotent stem cells (hiPSCs) offer powerful opportunities to study development and design future regenerative therapies. Directing their differentiation, however, requires carefully tuned signals. In a study published in Biomaterials, researchers from Aix-Marseille Université, CNRS, directed by Rosanna Dono at IBDM in collaboration with Patrick Chames and Brigitte Kerfelec have developed a new tool that targets human Glypican-4 (hGPC4) – a key cell-surface regulator of developmental pathways.
A targeted approach
hGPC4 has long been recognised as an important modulator of signalling at the cell surface, but tools to specifically manipulate its activity in human cells have been limited. In this work, the authors developed RB1-Fc, a conformation-specific Fc-fusion nanobody designed to recognise hGPC4 with high precision.
Results. When applied to hiPSCs, RB1-Fc was found to promote stem-cell differentiation, mirroring the effect observed when hGPC4 expression is reduced. This suggests that RB1-Fc can act as a functional probe to modulate hGPC4-dependent pathways, and study how this proteoglycan shapes cell fate decisions.
Expanding the toolkit
By offering selective access to hGPC4 function, RB1-Fc opens opportunities to dissect how this proteoglycan shapes cell behaviour and fate decisions. Beyond its utility as a molecular tool, this approach may ultimately contribute to refining protocols for tissue engineering and regenerative medicine. Over time, hGPC4 has also emerged as a promising diagnostic and therapeutic target for a broad spectrum of developmental and neurological disorders, as well as cancer, due to its involvement in multiple signalling pathways and disease-relevant biological processes. Therefore, these nanobodies open new avenues for targeting hGPC4 in disorders associated with dysregulated hGPC4 activity. This study represents an important step forward in understanding how extracellular regulators such as hGPC4 influence human development – and highlights the growing repertoire of innovative molecular tools for exploring human development, diseases mechanisms, and future regenerative medicine.
To know more
Bonjean R, Cuciniello R, Kerfelec B, Chames P, Dono R. Functional targeting of Glypican-4 by a conformation-specific single-domain antibody. Biomaterials. 2025 Nov 21;328:123864.
