Biology subjects

Martinez-Morga, M.

Publications and source records attributed to Martinez-Morga, M..

3 recordsLinked to original sources

bioRxiv2026

The direct conversion of human somatic cells into neural-like cells involves a transition through a transient intermediate state.

BackgroundDirect conversion of human somatic cells into functional neurons could offer a faster way to generate patient-specific neurons for use in regenerative medicine, disease modelling, and drug development. Although it has been reported that neuronal direct reprogramming bypasses the intermediate pluripotent state, no reports have included time-lapse experiments, potentially overlooking transient intermediate states. Recent studies have shown that the conversion of human mesenchymal stromal cells (hMSCs) into neuron-like cells involves a transition through a transient intermediate state. Therefore, further research is needed to fully understand the process by which human somatic cells can become neurons without cell division. In this study we investigates whether direct neuronal reprogramming of human bone marrow-derived MSC (hBM-MSCs), dental pulp-derived MSC (hDP-MSCs), and adult human dermal fibroblasts (HDFa), involves a transient intermediate state, and sought to further validate the neuronal identity of hMSC-derived induced neurons. MethodsIn this study, we conducted time-lapse experiments to observe the transformation of hBM-MSCs, hDP-MSCs and HDFa, into neurons using a small-molecule-based direct reprogramming protocol. Cellular and ultrastructural changes were further characterized by confocal and electron microscopy. ResultsDirect conversion of hBM-MSCs, hDP-MSCs and HDFa into neuron-like cells occurred rapidly and in absence of cell division. Time-lapse analyses revealed that reprogramming proceeds through a transient intermediate state characterized by distinct morphological changes and dynamic nuclear remodelling. Furthermore, we found that neuron-like cells derived from hBM-MSCs and hDP-MSCs exhibit neuronal polarization, expressed specific neuronal and synaptic markers, formed interconnected cellular networks, and exhibited functional plasticity, providing further evidence that hMSCs can become functional neurons. ConclusionsThis study provides clear evidence that the direct neuronal reprogramming process involves a transition through an intermediate, transient state. Our findings also provide further evidence that hMSCs can become functional neurons. In summary, our work provides new insights into the direct neuronal reprogramming process, which is essential for advancing both developmental biology and regenerative medicine.

neuroscience↗

bioRxiv2021

Differentiation of human adult-derived stem cells towards a neural lineage involves a de-differentiation event prior to re-differentiation to neural phenotypes

Although it has been reported that mesenchymal stem cells isolated from adult tissues can be induced to overcome their mesenchymal fate and transdifferentiate into neural cells, the findings and their interpretation have been challenged. The main argument against this process is that the cells rapidly adopt neuron-like morphologies through retraction of the cytoplasm rather than active neurite extension. In this study, we examined the sequence of biological events during neural differentiation of human periodontal ligament-derived stem cells (hPDLSCs), human bone marrow-derived stem cells (hBMSCs) and human dental pulp-derived stem cells (hDPSCs) by time-lapse microscopy. We have demonstrated that hPDLSCs, hBMSCs and hDPSCs can directly differentiate into neuron-like cells without passing through a mitotic stage and that they shrink dramatically and change their morphology to that of neuron-like cells through active neurite extension. Furthermore, we observed micronuclei movement and transient cell nuclei lobulation concurrent to in vitro neurogenesis from hBMSCs and hDPSCs. Our results demonstrate that the differentiation of hPDLSCs, hBMSCs and hDPSCs towards a neural lineage occurs through a de-differentiation step followed by re-differentiation to neural phenotypes, and therefore we definitively confirm that the rapid acquisition of the neural phenotype is via a differentiation trait.

neuroscience↗

bioRxiv2018

Nuclear polymorphism and non-proliferative adult neurogenesis in human neural crest-derived cells.

Self-renewal and lineage regulation of neural stem cells in the adult mammalian brain (aNSCs) are still far from been understood. Although previous studies have reported that some aNSCs in neurogenic niches showed irregular nuclei, their functional significance remains elusive. We used neural crest-derived human periodontal ligament stem cells (hPDLSCs) as an in vitro cell model of neurogenesis to investigate the functional significance of nuclear polymorphisms. Here, we show that hPDLSCs-derived neurons are not directly generated through cell division from stem cells. In fact, the cell shape of neural precursors is reset and start their neuronal development as round spheres. The hPDLSCs-derived neurons gradually adopted a complex morphology by forming several processes, that grew and arborized, adquiring dendritic-like and axonal-like identities, giving rise to a variety of neuron-like morphologies. To our knowledge, this article provides the first observation of these morphological events during in vitro neurogenesis and neuron polarization in human aNCSCs, and we have discovered a transient cell nuclei lobulation coincident to in vitro neurogenesis, without being related to cell proliferation. We observed that small DNA containing structures move within the cell to specific directions and temporarily form lobed nuclei. Morphological analysis also reveals that neurogenic niches in the adult mouse brain contains cells with nuclear shapes highly similar to those observed during in vitro neurogenesis from hPDLSCs. Our results provide strong evidence that neuronal differentiation from aNSCs may also occur during in vivo adult mammalian neurogenesis without being related to cell proliferation. In addition, we demonstrate that hPDLSCs-derived neurons display a sequence of morphologic development highly similar to those observed in primary neuronal cultures derived from rodent brains during neurogenesis, providing strong evidence that it is possible to reproduce neurogenic processes and obtain neurons from hPDLSCs. Beyond the central nervous system, the presence of lobed nuclei has been reported in most blood and immune cells, but the functional significance of multilobed nuclear structures is not yet stablished. Our results suggest that multilobed nuclear structures is associated to nuclear movement within the cell.

neuroscience↗