Biology subjects

Nilsson, F.

Publications and source records attributed to Nilsson, F..

6 recordsLinked to original sources

bioRxiv2026

Transient matrix remodeling during direct cell-fate reprogramming enables self-assembly of dense neuronal niches

Native tissues are characterized by high cellular density and continuous reciprocal interactions between cells and the extracellular matrix (ECM), yet recreating these features in vitro remains a major challenge. Current three-dimensional (3D) culture systems typically capture either dense cell-cell interactions or a defined ECM environment, but rarely both. Here, we introduce a strategy that exploits direct fibroblast-to-neuron reprogramming to decouple microenvironment formation from final cell identity. Human dermal fibroblasts were embedded in collagen microgels, where their intrinsic matrix-remodeling capacity drove rapid ECM compaction. Concurrently, the contractile fibroblasts were converted into induced neurons (iN), generating densely packed neuronal microcultures within a remodeled collagen matrix. This approach transforms a defining function of the starting cell type into a mechanism for engineering the microenvironment of the target cell type. The resulting iN-microgels combine high cell density, defined ECM composition, and tunable biophysical properties in a scalable microscale format. By coupling matrix remodeling with cell-fate conversion, our platform establishes a general framework for engineering tissue-like microenvironments and reveals how dynamic 3D extracellular contexts can be integrated into direct cell reprogramming.

bioengineering↗

bioRxiv2023

Injectable 3D microcultures enable intracerebral transplantation of mature neurons directly reprogrammed from patient fibroblasts

Direct reprogramming of somatic cells into induced neurons (iNs) has become an attractive strategy for the generation of patient-specific neurons for disease modeling and regenerative neuroscience. To this end, adult human dermal fibroblasts (hDFs) present one of the most relevant cell sources. However, iNs generated from adult hDFs using two-dimensional (2D) cultures poorly survive transplantation into the adult brain in part due to the need for enzymatic or mechanical cellular dissociation before transplantation. Three-dimensional (3D) culturing methodologies have the potential to overcome these issues but have largely been unexplored for the purposes of direct neuronal reprogramming. Here we report a strategy for direct in vitro reprogramming of adult hDFs inside suspension 3D microculture arrays into induced DA neurospheroids (iDANoids). We show that iDANoids express neuronal and DA markers and are capable of firing mature action potentials and releasing dopamine. Importantly, they can be gently harvested and transplanted into the brain of a Parkinsons disease rat model to reproducibly generate functionally integrated neuron-rich grafts. The 3D culturing approach presented here thus eliminates a major bottleneck in direct neuronal reprogramming field and, due to its simplicity and versatility, could readily be adapted as a culturing platform used for a broad range of transplantation studies as well as disease modeling.

neuroscience↗

bioRxiv2021

Age-related pathological impairments in induced neurons derived from patients with idiopathic Parkinson's disease

Understanding the pathophysiology of Parkinsons disease has been hampered by the lack of models that recapitulate all the critical factors underlying its development. Here, we generated functional induced dopaminergic neurons (iDANs) that were directly reprogrammed from adult human dermal fibroblasts of patients with idiopathic Parkinsons disease to investigate diseaserelevant pathology. We show that iDANs derived from Parkinsons disease patients exhibit lower basal chaperone-mediated autophagy as compared to iDANs of healthy donors. Furthermore, stress-induced autophagy resulted in an accumulation of macroautophagic structures in induced neurons (iNs) derived from Parkinsons disease patients, independently of the specific neuronal subtype but dependent on the age of the donor. Finally, we found that these impairments in patient-derived iNs lead to an accumulation of phosphorylated alpha-synuclein, a hallmark of Parkinsons disease pathology. Taken together, our results demonstrate that direct neural reprogramming provides a patient-specific model to study aged neuronal features relevant to idiopathic Parkinsons disease.

neuroscience↗

bioRxiv2020

Serotype has a significant impact on the virulence of 7th pandemic Vibrio cholerae O1

Of over 200 different identified Vibrio cholerae serogroups only the O1 serogroup is consistently associated with endemic and epidemic cholera disease. The O1 serogroup has two serologically distinguishable variants, the Ogawa and Inaba serotypes, which differ only by a methyl group present on the terminal sugar of the Ogawa O-antigen but absent from Inaba strains. This methylation is catalyzed by a methyltransferase encoded by the wbeT gene, which in Inaba strains is disrupted by mutation. It is currently thought that there is little difference between the two serotypes. However, here we show, using isogenic pairs of O1 El Tor V. cholerae, that Inaba strains show significantly different patterns of gene expression and are significantly less able than the corresponding Ogawa strains to cause cholera in an infant mouse infection model. Our results suggest that changes in gene expression resulting from the loss of the wbeT gene lead to reduced virulence and possibly also reduced survival fitness outside the human host. Author SummaryThe bacterium Vibrio cholerae causes the pandemic diarrheal disease cholera. Despite many identified serotypes of V. cholerae only one, O1, causes pandemic cholera. The O1 serotype of pandemic V. cholerae has two distinguishable variants (called Ogawa and Inaba) long considered to be clinically and epidemiologically equivalent. Cholera outbreaks consist only of one the two variants at any time. In general, Ogawa strains cause the majority of outbreaks with relatively short-lived Inaba outbreaks occurring sporadically. We have suggested earlier that Inaba outbreaks occur during periods of environmental selective pressure against the Ogawa serotype. We demonstrate here that the two variants are not clinically equivalent. The Ogawa serotype is better able to respond to infection in an animal model by up regulating the expression of virulence genes essential for disease development. We suggest that this phenomenon is the result of wider ranging differences in gene expression resulting from the mutation that converts Ogawa into Inaba strains, and may help to explain the dominance of the Ogawa serotype in nature.

microbiology↗

bioRxiv2020

Single cell transcriptional and functional analysis of human dopamine neurons in 3D fetal ventral midbrain organoid like cultures

Transplantation of midbrain dopamine (DA) neurons for the treatment of Parkinsons disease (PD) is a strategy that has being extensively explored and clinical trials using fetal and stem cell-derived DA neurons are ongoing. An increased understanding of the mechanisms promoting the generation of distinct subtypes of midbrain DA during normal development will be essential for guiding future efforts to precisely generate molecularly defined and subtype specific DA neurons from pluripotent stem cells. In this study, we used droplet-based scRNA-seq to transcriptionally profile a large number of fetal cells from human embryos at different stages of ventral midbrain (VM) development (6, 8, and 11 weeks post conception). This revealed that the emergence of transcriptionally distinct cellular populations was evident already at these early timepoints. To study late events of human DA differentiation and functional maturation, we established a primary fetal 3D culture system that recapitulates key molecular aspects of late human DA neurogenesis and sustains differentiation and functional maturation of DA neurons in a physiologically relevant cellular context. This approach allowed us to define the molecular identities of distinct human DA progenitors and neurons at single cell resolution and construct developmental trajectories of cell types in the developing fetal VM. Overall these findings provide a unique transcriptional profile of developing fetal VM and functionally mature human DA neurons, which can be used to quality control stem cell-derived DA neurons and guide stem cell-based therapies and disease modeling approaches in PD.

neuroscience↗

bioRxiv2019

Hygiene Hampers Competitive Release Of Resistant Bacteria In The Commensal Microbiota

AO_SCPLOWBSTRACTC_SCPLOWGood hygiene, in both health care and the community, is central to containing the rise of antibiotic resistance, as well as to infection control more generally. But despite the well-known importance, the ecological mechanisms by which hygiene affects resistance evolution remain obscure. Using metacommunity ecology theory, we here propose that hygiene attenuates the effect of antibiotic selection pressure. Specifically, we predict that hygiene limits the scope for antibiotics to induce competitive release of resistant bacteria within treated hosts, and that this is due to a modulating effect of hygiene on the distribution of resistant and sensitive strains in the host population. We show this in a mathematical model of bacterial metacommunity dynamics, and test the results against data on antibiotic resistance, antibiotic treatment, and the use of alcohol-based hand rub in long-term care facilities. Our results underscore the importance of hygiene, and point to a concrete way to weaken the link between antibiotic use and increasing resistance.

evolutionary biology↗