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Reprogramming cellular identity in vivo

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Delineating chromatin accessibility re-patterning at single cell level during early stage of direct cardiac reprogramming

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Summary: Direct conversion of cardiac fibroblast into induced cardiomyocytes by cardiac transcription factors shows promise for regenerative medicine. Transcriptome remodelling during cardiac reprogramming is driven by chromatin landscape alteration. The study used single-cell ATAC-seq to identify early chromatin accessibility changes and discovered Smad3 as a bimodal TF in cardiac reprogramming. Integrative analysis with scRNA-seq data revealed active TFs important for iCM conversion and global rewiring of cis-regulatory interactions of cardiac genes along the reprogramming trajectory.

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Statistically derived geometrical landscapes capture principles of decision-making dynamics during cell fate transitions

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Summary: In this study, a quantitative dynamical landscape was constructed to accurately predict cell fate, and two archetypal patterns of cell decisions in development were identified.

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Article Cell & Tissue Engineering

Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs

Kitra Cates et al.

Summary: This study revealed the activity of miR-9/9* and miR-124 as reprogramming agents in eradicating fibroblast identity and promoting direct conversion into motor neurons. Inhibition of KLF-family transcription factors downstream of miR-9/9*-124 is crucial for erasing fibroblast fate, while the subsequent acquisition of neuronal identity requires upregulation of RN7SK to induce chromatin accessibility and neuronal gene activation. Our research defines deterministic components in the microRNA-mediated reprogramming cascade.

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Revisiting astrocyte to neuron conversion with lineage tracing in vivo

Lei-Lei Wang et al.

Summary: Recent studies have shown that in vivo cell fate conversions may not actually be converting astrocytes into neurons, but instead utilizing endogenous neurons. Lineage tracing strategies are necessary to accurately track the origin of converted cells, highlighting the importance of applying stringent tracing techniques in studies of cell fate conversions in vivo.
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Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial lobe

Celia Lentini et al.

Summary: Reprogramming brain-resident glial cells into induced neurons (iNs) has shown potential as a disease-modifying strategy to reduce seizures in therapy-resistant epilepsy, as demonstrated in a mouse model of mesial temporal lobe epilepsy (MTLE).

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Epigenetic memory in reprogramming

Eva Hoermanseder

Summary: The stability of cell fates during development involves differentiation, cell memory, and the potential for reprogramming. Epigenetic mechanisms play a crucial role in maintaining stable cell-fate memory and resistance to reprogramming, highlighting the importance of understanding these processes in regenerative medicine.

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A quantitative model of cellular decision making in direct neuronal reprogramming

Adriaan Merlevede et al.

Summary: Direct reprogramming of adult skin fibroblasts into neurons is controlled by interacting gene regulators, and the dynamics of these interactions are crucial for cellular decision making. A quantitative model of the governing gene regulatory system, supported by mRNA expression measurements, was proposed to capture the accurate gene interaction dynamics and predict the outcome of various experiments. Experimental validation demonstrated the importance of nPTB feedback for successful neural conversion, and a novel analytical technique was introduced to dissect system behavior and reveal the influence of individual factors on gene expression. Overall, computational analysis proves to be a powerful tool for understanding the mechanisms of direct (neuronal) reprogramming and improving cell conversion strategies in the future.

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In vivo reprogramming of NG2 glia enables adult neurogenesis and functional recovery following spinal cord injury

Wenjiao Tai et al.

Summary: Adult neurogenesis is crucial for brain homeostasis and recovery from neurogenic insults. Spinal cord injury (SCI) can activate latent neurogenic potential of NG2 + glial cells through ectopic SOX2 expression, leading to the generation of new neurons and functional recovery. This study demonstrates the potential for regenerative medicine by leveraging the neurogenic capacity of somatic glial cells.

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NeuroD1 induces microglial apoptosis and cannot induce microglia-to-neuron cross-lineage reprogramming

Yanxia Rao et al.

Summary: This study found that NeuroD1 cannot convert microglia to neurons, instead inducing microglial cell death, hence unable to achieve cross-lineage reprogramming. Lineage tracing revealed virus leakage, confounding the results of glia-to-neuron conversion.

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Direct cell reprogramming: approaches, mechanisms and progress

Haofei Wang et al.

Summary: Direct reprogramming converts cells from one lineage into another without going through a pluripotent state, and it is a promising strategy for generating functional cells for therapeutic purposes. Recent advancements include using defined factors for lineage conversion, enhancing reprogrammed cell maturation, and addressing challenges in in vivo direct reprogramming for translational applications.

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Formation and integration of new neurons in the adult hippocampus

Annina Denoth-Lippuner et al.

Summary: In this Review, recent advances in adult hippocampal neurogenesis in rodents are presented, focusing on the distinct developmental steps and regulatory mechanisms, as well as the impact of newborn neurons on brain function.

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Efficient stimulation of retinal regeneration from Muller glia in adult mice using combinations of proneural bHLH transcription factors

Levi Todd et al.

Summary: The combination of Ascl1 and Atoh1 transcription factors is remarkably efficient at stimulating neurogenesis in targeted Müller glia cells, even in the absence of retinal injury. Using electrophysiology and single-cell RNA sequencing, the study demonstrates that this combination can generate a diversity of retinal neuron types. The results provide proof of principle that combinations of developmental transcription factors can substantially enhance glial reprogramming to neurons and expand the variety of regenerated cell fates.

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Article Cell & Tissue Engineering

Donor cell memory confers a metastable state of directly converted cells

Kee-Pyo Kim et al.

Summary: By transducing an optimized transcription factor combination into a permissive donor phenotype, pericyte-derived iOPCs (PC-iOPCs) can overcome the limitations of inefficient generation and limited expansion and differentiation competence. PC-iOPCs are stably expandable and functionally myelinogenic with high differentiation competence.

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The histone reader PHF7 cooperates with the SWI/SNF complex at cardiac super enhancers to promote direct reprogramming

Glynnis A. Garry et al.

Summary: The histone reader PHF7 cooperates with the SWI/SNF complex at cardiac super enhancers to increase accessibility to core cardiac transcription factors, facilitating direct cardiac reprogramming.

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Astrocytes and neurons share region-specific transcriptional signatures that confer regional identity to neuronal reprogramming

Alvaro Herrero-Navarro et al.

Summary: Neural cell diversity is crucial for assigning specific functions to different brain regions. This study reveals that neurons and astrocytes in the neocortex and thalamus share region-specific transcriptional and epigenetic signatures, which can distinguish cells across different brain regions and within substructures. Common nucleus-specific progenitors for neurons and astrocytes may exist in distinct thalamic nuclei, suggesting a shared molecular signature among cells in these brain regions.

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Direct reprogramming with Sendai virus vectors repaired infarct hearts at the chronic stage

Mari Isomi et al.

Summary: Adult hearts have limited regenerative capacity, but direct reprogramming of cardiac fibroblasts into induced cardiomyocytes with GMT may have significant potential for cardiac repair. Studies have shown that SeV-GMT reprogramming in mouse hearts after acute MI can improve cardiac function.

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Direct in vivo reprogramming with non-viral sequential targeting nanoparticles promotes cardiac regeneration

Qiaozi Wang et al.

Summary: This study developed a non-viral biomimetic system for cardiac regeneration by coating neutrophil-mimicking membranes on mesoporous silicon nanoparticles loaded with microRNA1, 133, 208, and 499. The system utilized the inflammation-homing ability of neutrophil membrane protein and FH peptide's high affinity to tenascin-C produced by CFs for targeted delivery of miRCombo, leading to reprogramming of resident CFs into iCMs and improved cardiac function in a mouse model of myocardial ischemia/reperfusion injury.

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Molecular diversity of diencephalic astrocytes reveals adult astrogenesis regulated by Smad4

Stefanie Ohlig et al.

Summary: Astrocytes exhibit diverse gene expression states related to distinct functions, with some subsets being more widespread while others are regionally restricted. The study also reveals the novel concept of low-level proliferation of astrocytes in the adult diencephalon, with Smad4 identified as a key regulator.

EMBO JOURNAL (2021)

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Transient astrocyte-like NG2 glia subpopulation emerges solely following permanent brain ischemia

Denisa Kirdajova et al.

Summary: NG2 glia exhibit diverse proliferation and differentiation potential in various brain disorders, with distinct changes observed in mice with eye diseases. Single-cell analysis reveals the presence of different subpopulations within NG2 glia.
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Highly Efficient MicroRNA Delivery Using Functionalized Carbon Dots for Enhanced Conversion of Fibroblasts to Cardiomyocytes

Lei Yang et al.

Summary: This study successfully utilized branched polyethyleneimine (BP) coated nitrogen-enriched carbon dots (BP-NCDs) as carriers loaded with microRNAs-combo (BP-NCDs/MC), achieving direct reprogramming of fibroblasts into induced cardiomyocytes and effective recovery of cardiac function after myocardial infarction. This novel strategy provides a promising direction for cardiac regeneration and disease therapy through safe and effective microRNA delivery nanoplatforms based on carbon dots.

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Heterogeneity of neurons reprogrammed from spinal cord astrocytes by the proneural factors Ascl1 and Neurogenin2

J. Kempf et al.

Summary: Astrocytes can be transformed into new neurons, but the neurogenic cascades triggered within astrocytes from different brain regions remain poorly understood. Ascl1 and Neurog2 initially induce different neurogenic programs in astrocytes which eventually converge into a V2 interneuron-like state. Patch-seq analysis reveals that, apart from K-channels, there is no clear overall correlation between the functional properties and transcriptome of induced neurons.

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Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

Suhong Sun et al.

Summary: This study successfully converted adult mouse cochlear supporting cells into Prestin+ OHC-like cells through the induction of two key transcription factors. Single-cell RNA sequencing showed significant changes in gene expression, indicating a more advanced differentiation status of these OHC-like cells. This efficient approach opens up possibilities for in vivo cochlear repair through cell transdifferentiation.
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Restoration of Visual Function and Cortical Connectivity After Ischemic Injury Through NeuroD1-Mediated Gene Therapy

Yu Tang et al.

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