Laminin γ3 plays an important role in retinal lamination, photoreceptor organisation and ganglion cell differentiation

Abstract

Laminins are heterotrimeric glycoproteins of the extracellular matrix. Eleven different laminin chains have been identified in vertebrates. They are ubiquitously expressed in the human body, with a distinct tissue distribution. Laminin expression in neural retina and their functional role during human retinogenesis is still unknown. This study investigated the laminin expression in human developing and adult retina, showing laminin α1, α5, β1, β2 and γ1 to be predominantly expressed in Bruch’s membrane and the inner limiting membrane. Laminin-332 and laminin γ3 expression were mainly observed in the neural retina during retinal histogenesis. These expression patterns were largely conserved in pluripotent stem cell-derived retinal organoids. Blocking of laminin γ3 function in retinal organoids resulted in the disruption of laminar organisation and synapse formation, the loss of photoreceptor organisation and retinal ganglion cells. Our data demonstrate a unique temporal and spatial expression for laminins and reveal a novel role for laminin γ3 during human retinogenesis.

Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective

“…Multiple recent studies have directly compared human fetal retina with human stem cell-derived retinal organoids, analyzing their morphology or transcriptome, or both [54,[147][148][149]. Additionally, a large body of research exists regarding the morphology and transcriptome of either human fetal retina [8,40,41,[150][151][152][153][154][155][156][157][158][159][160] or human stem cell-derived retinal organoids [58,141,142,[161][162][163][164][165][166][167][168][169][170].…”

“…However, this varied between protocols and degeneration of the inner retina in ageing organoids may also play a factor [148,162,167,170,171,178]. Interestingly, Dorgau et al (2018) showed that blocking of the extracellular matrix protein Laminin γ3 in late-stage retinal organoids led to the disruption of ribbon synapse marker Bassoon. This may be due to the significant disruption of Müller glial cell end feet at the inner limiting membrane [148].…”

“…Interestingly, Dorgau et al (2018) showed that blocking of the extracellular matrix protein Laminin γ3 in late-stage retinal organoids led to the disruption of ribbon synapse marker Bassoon. This may be due to the significant disruption of Müller glial cell end feet at the inner limiting membrane [148]. Wahlin et al (2017) showed that both excitatory (L-aspartate, glutamate) and inhibitory (GABA, glycine) neurotransmitters of the retina were present in Wk 43 (DD300) hiPSC-derived retinal organoids.…”

“…Degeneration of the inner retina is likely due to the lack of access by medium components, particularly as the retina thickens during development. Furthermore, misregulation of ECM components in human stem cell-derived retinal organoids may significantly affect their correct lamination [148]. Reproducibility and staging of human retinal organoids is also an important consideration particular as we further explore their use in developmental studies and disease modelling [207].…”

Partially Differentiated Neuroretinal Cells Promote Maturation of the Retinal Pigment Epithelium

“…36 In this report, we improved the scaffold by decorating it with laminin-521, which promotes cell proliferation in stem cell niches. [37][38][39][40][41][42][43] Laminin-5xx (laminins with α5 subunits) is found in the inner limiting membrane throughout fetal development. 42 The scaffold-cultured RPCs were co-cultured with RPE, and we examined the effects of co-culture on the differentiation of each "tissue.…”