Biology subjects

Heinrich, C.

Publications and source records attributed to Heinrich, C..

5 recordsLinked to original sources

bioRxiv2025

The Pioneer Transcription Factor Oct4 Differentially Co-opts Bcl11a and Bcl11b to Regulate Reprogramming to Pluripotency

Pioneer transcription factors (TFs) orchestrate development, reprogramming, and cancer. Yet, the molecular mechanisms by which they cooperate with endogenous TFs and chromatin to trigger cell fate conversions remain largely unknown. Here, we identified antagonistic functions in reprogramming to pluripotency for the two paralogous somatic zinc finger TFs Bcl11a and Bcl11b. We reveal that Bcl11a and Bcl11b are initially co-expressed in mouse embryonic fibroblasts and then segregate in cellular intermediates respectively prone or refractory to reprogramming, transdifferentiation, and oncogenic transformation. They exert opposite functions - with Bcl11a promoting and Bcl11b hindering - the efficacy of induced pluripotent stem cells generation. During reprogramming, we uncover that Bcl11b safeguards cellular identity by persistently binding to differentiation genes with Runx1 in refractory intermediates. In contrast, in reprogramming intermediates, Bcl11a interacts with Oct4 and is initially displaced from MEF enhancers. Bcl11a then binds transiently and contributes to activate the E3 ubiquitin ligase Pja1 that regulates Smad3, thus promoting mesenchymal-epithelial transition and constraining senescence. Collectively, our work unveils how the differential repurposing of paralogous TFs by Oct4 orchestrates reprogramming to pluripotency.

cell biology↗

bioRxiv2025

Mx1-Cre-mediated Rac1 knockout confers multiple protective effects against anthracycline-induced acute normal tissue injury

Pharmacological data point to RAC1 as promising target for protection against anthracycline-induced cardiotoxicity, yet supporting genetic evidence is limited. Moreover, the relevance of RAC1 for cross-organ injury and cross-agent-induced normal tissue toxicity is unknown. Here, we employed a Mx1-Cre-based mouse model that enables an inducible Rac1 knockout across different organs in order to comparatively analyze the influence of RAC1 on doxorubicin (DOX) and cisplatin (CisPt)-induced acute stress responses of the heart, kidney and liver. Following DOX treatment, the extend of DNA-double strand break (DSB) formation and the percentage of apoptotic cells were reduced in all three organs (i.e. heart, liver, kidney) of RAC1 deficient (Rac1-/-) animals as compared to the wildtype control (Rac1+/+). By contrast, in the absence of RAC1, CisPt-induced DNA damage was reduced only in the liver and the frequency of CisPt-stimulated apoptotic cell death remained unaffected by the Rac1 status in all organs. These findings demonstrate a strikingly organ- and agent-specific relevance of RAC1-regulated mechanisms for normal tissue damage evoked by genotoxic anticancer therapeutics. Accordingly, protein levels of phosphorylated DNA damage response (DDR)-related factors were also reduced in the kidney and liver of DOX treated Rac1-/- animals, but not in the heart. Yet, DOX-triggered mRNA expression of surrogate markers related to inflammation, fibrosis and senescence was preferentially reduced in the heart and kidney of Rac1 deficient mice. Taken together, RAC1 plays a so far unknown distinct role in the pathophysiology of anticancer drug-induced normal tissue damage by influencing DNA damage formation, activation of DDR, apoptosis induction as well as inflammation-, fibrosis- and senescence-associated responses in a pronounced agent- and organ-specific manner. Targeting of RAC1 appears particularly effective in the context of anthracycline-based therapeutic regimen for conferring broad organoprotection to both the heart and detoxifying organs. Translational PerspectiveThis study provides the first genetic evidence identifying RAC1 as a critical mediator of anthracycline-induced cardiac, hepatic and renal injury. We demonstrate that genetic deletion of Rac1 alleviates chemotherapy-induced DNA damage, apoptosis, and stress responses related to senescence, fibrosis, and inflammation in an agent- and organ-specific manner. These findings highlight RAC1 as a putatively clinically relevant target for the development of organoprotective pharmacological strategies aiming to improve the tolerability of anthracycline- and cisplatin-based therapeutic regimen and, accordingly, enhancing the quality of life and prognosis of tumor patients.

pharmacology and toxicology↗

bioRxiv2025

Modeling the acutely injured brain environment in vitro.

A major challenge to study the regenerative potential of the injured brain is the limited access to this organ in vivo. To address this, we developed an innovative gliosis model that, although established in vitro, originates from a genuine injury in vivo. The model relies on reactive glia acquiring enhanced adhesion, facilitating their rapid adaptation to in vitro conditions, where it faithfully recapitulates key features of brain injury. These include a secretome associated with injury pathways, degenerative responses like neuronal death and neuroinflammation, and regenerative processes such as progenitor proliferation, recruitment and commitment to oligodendrocytes. Moreover, the exposure of adult glial cells to this culture medium recapitulates their acquisition of multipotency observed in both mouse and human injured brains. Finally, our approach allows studying glia-to-neuron reprogramming, a process challenging to tackle in vivo. Consequently, we present a novel tool for exploring stem cell dynamics and regenerative behaviors in CNS pathology.

neuroscience↗

bioRxiv2022

Single cell analysis of the dorsal V-SVZ reveals differential quiescence of postnatal pallial and subpallial neural stem cells driven by TGFbeta/BMP-signalling

The ventricular-subventricular zone (V-SVZ) is the largest neurogenic region of the postnatal forebrain, containing neural stem cells (NSCs) that emerge from both the embryonic pallium and subpallium. Despite of this dual origin, glutamatergic neurogenesis declines rapidly after birth, while gabaergic neurogenesis persists throughout life. Here, we performed single-cell RNA-sequencing (scRNA-Seq) of the postnatal dorsal V-SVZ for unravelling the mechanisms leading to pallial lineage germinal activity silencing. We identify cell lineage-specific NSCs primed for the generation of neurons or glial cells, as well as a large population of so far uncharacterized quiescent NSCs (qNSC). Pallial qNSCs enter a state of deep quiescence, characterized by persistent TGFbeta/BMP signalling, reduced transcriptional activity and Hopx expression, whilst in contrast, subpallial qNSCs remain transcriptionally primed for activation. Induction of deep pallial quiescence is paralleled by a rapid blockade of glutamatergic neuron production and differentiation. Finally, manipulation of the TGFbeta/BMP receptor Bmpr1a demonstrate its key role in mediating these effects at early postnatal times. Together, our results highlight a central role of TGFbeta/BMP-signalling in synchronizing quiescence induction and blockade of neuronal differentiation to rapidly silence pallial germinal activity after birth.

neuroscience↗

bioRxiv2020

Evidence of progenitor cell lineage rerouting in the adult mouse hippocampus

Cell lineage in the adult hippocampus comprises multipotent and neuron-committed progenitors. In the present work, we fate-mapped neuronal progenitors using Dcx-CreERT2 and CAG-CAT-EGFP double-transgenic mice (cDCX/EGFP). We show that three days after tamoxifen-mediated recombination in cDCX/EGFP adult mice, GFP+ cells in the dentate gyrus co-expresses DCX and about 6% of these cells are proliferative neuronal progenitors. After 30 days, 20% of GFP+ generated from these progenitors differentiate into GFAP+ astrocytes. Administration of the chemoconvulsants kainic acid (KA) or pilocarpine (PL) led to a significant increase in the number of GFP+ cells in both ipsi and contralateral dentate gyrus. However, while PL favored the differentiation of neurons in both ipsi- and contralateral sides, KA stimulated neurogenesis only in the contralateral side. In the ipsilateral side, KA injection led to an unexpected increase of astrogliogenesis in the Dcx-lineage. These different effects of KA and PL in the Dcx-lineage are associated with distinct alterations of the parvalbuminergic plexus and inflammatory responses in the hippocampi. Finally, we also observed a small number of GFP+/GFAP+ cells displaying radial-glia morphology ipsilaterally 3 days after KA administration, indicating that Dcx-progenitors could regress to a multipotent stage. Altogether, our data suggest that cell lineage in the adult hippocampus is not unidirectional and can be modulated by environmental signals.

neuroscience↗