Scaramuzza, L. | Search bioRxiv

bioRxiv2025

Cografting strategies uncover cell type dependent regulation of dopamine neuron specification and functional maturation in a pre clinical model of Parkinson`s Disease

Parkinsons disease (PD), the second most common neurodegenerative disorder, is characterized by the progressive loss of A9 dopaminergic neurons in the substantia nigra, leading to dopamine (DA) depletion in the striatum and subsequent motor symptoms. Transplantation of ventral midbrain-patterned DA (vmDA) progenitors derived from human pluripotent stem cells, aimed at restoring DA neurotransmission in the striatum, is being developed and currently explored in ongoing clinical trials. One factor that may improve the maturation and fate determination of DA neurons in vivo is the intercellular communication within the graft environment, ultimately affecting the therapeutic outcome. In this study, we co-transplanted vmDA progenitors with either glial, ventral forebrain or striatal progenitors into a preclinical xenograft PD model to investigate how these interactions shape the development, maturation, and function of therapeutic DA neurons. Our findings show that co-grafts with ventral forebrain progenitors increase the yield of DA neurons and also promote their functional maturation. Furthermore, we demonstrated that co-grafts with striatal neurons promote functional maturation and the acquisition of DA subtype identity. From these data, we identified EBF3 and PBX3 as candidate transcription factors directing DA neuron maturation and subtype specification, and then functionally validated their role in brain organoids. Taken together, our data highlight that the cellular microenvironment, including specific interactions with neighbouring cells, guides in vivo DA neuron specification and maturation. These findings provide a foundation for developing more refined and effective cell preparations for replacement therapy in PD, and define a conceptual framework that could inform stem cell-based strategies for other neurodegenerative diseases.

neuroscience↗

bioRxiv2020

The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes

Mecp2 deficiency, the gene responsible for Rett syndrome (RTT), affects brain maturation by impairing neuronal activity, transcription and morphology. These three elements are physiologically linked in a feed-forward cycle where neuronal activity modulates transcription and morphology to further increase network maturity. We hypothesized that the reduced activity displayed by maturing Mecp2 null neurons during development could perturb such cycle, sustaining an improper transcriptional program that, ultimately, impairs neuronal maturation. Accordingly, we show that by enhancing activity within an early time window, Ampakine redirects, in vitro, the development of null neuronal networks towards more physiological routes. Similarly, the administration of the drug to newborn null offspring delays the progression of symptoms, significantly prolonging life span. Our data highlights the role of altered neuronal activity during the establishment of Mecp2 null networks and the importance of such early defects to the typically poor maturity of RTT brain functions in adulthood. We propose the existence of an "early molecular phase" of Rett syndrome, a detailed description of which might disclose relevant targets for new rescue treatments.

neuroscience↗