Biology subjects

Lendengolts, D.

Publications and source records attributed to Lendengolts, D..

4 recordsLinked to original sources

bioRxiv2023

Small Extracellular Vesicles from Failing Heart Accelerate Tumor Growth

BackgroundMyocardial infarction (MI) and heart failure (HF) are associated with an increased incidence of cancer. The mechanism is complex and unclear. Here, we aimed to test our hypothesis that cardiac small extracellular vesicles (sEVs), particularly cardiac mesenchymal stromal cells-derived sEVs (cMSC-sEVs), contribute to the link between post-MI HF and cancer. MethodsWe purified and characterized sEVs from the whole heart and cultured cMSCs. Then, we analyzed cMSC-EV cargo and pro-neoplastic effects on several types of cancer cell lines, macrophages, and endothelial cells. Next, we modeled post-MI HF along with heterotopic and orthotopic lung and breast cancer tumors in mice. We used cMSC-sEV transfer to assess sEV biodistribution and its effect on tumor growth. Finally, we tested the effects of sEV depletion and spironolactone treatment on cMSC-EV release and tumor growth. ResultsPost-MI hearts, particularly cMSCs, produced more sEVs with pro-neoplastic cargo than non-failing hearts did. Proteomic analysis revealed unique protein profiles and higher quantities of tumor-promoting cytokines, proteins, and microRNAs in cMSC-sEVs from failing hearts. The pro-neoplastic effects of cMSC-sEVs varied with different types of cancer cells, substantially affecting lung cancer cells relative to other more aggressive cancer cell lines. We also found that post-MI cMSC-sEVs activated resting macrophages into pro-angiogenic and pro-tumorigenic states in vitro. At 28-day follow-up analysis, mice with post-MI HF developed larger lung tumors than did sham-MI mice. Adoptive transfer of cMSC-sEVs from failing hearts accelerated lung tumor growth, and biodistribution analysis revealed an accumulating cMSC- sEVs in tumor cells along with accelerated tumor cell proliferation. Significantly, sEV depletion reduced the tumor-promoting effects of HF, and adoptive transfer of cMSC-sEVs from failing hearts partially restored it. Finally, post-MI spironolactone treatment reduced the number of cMSC-sEVs and suppressed tumor growth during post-MI HF. ConclusionsFor the first time, we show that cardiac sEVs, specifically cMSC-sEVs from post-MI failing hearts, carry multiple pro-tumorigenic factors. Uptake of cMSC-sEVs by cancer cells accelerates tumor growth. Post-MI spironolactone treatment reduces the associated tumor growth. Thus, we provide new insight into the link between post-MI HF and cancer and propose a translational option to mitigate this deadly association.

cancer biology↗

bioRxiv2023

Circuit to target approach defines an autocrine myofibroblast loop that drives cardiac fibrosis

Fibrosis is a broad pathology of excessive scarring with substantial medical implications. The fibrotic scar is produced by myofibroblasts that interact with macrophages. Fibrosis is a complex process involving thousands of factors, therefore, to better understand fibrosis and develop new therapeutic approaches, it is necessary to simplify and clarify the underlying concepts. Recently, we described a mathematical model for a macrophage-myofibroblast cell circuit, predicting two types of fibrosis - hot fibrosis with abundant macrophages and myofibroblasts, and cold fibrosis dominated by myofibroblasts alone. To test these concepts and intervention strategies in a medically relevant system, we use a widely studied in-vivo injury model for fibrosis, myocardial infarction (MI). We show that cold fibrosis is the final outcome of MI in both mice and pigs and demonstrate that fibrosis can shift toward healing in regenerative settings. MI begind with an increase of myofibroblasts and macrophages, followed by macrophage decline leading to persistent cold fibrosis (only myofibroblasts). During this process, fibroblasts, unlike macrophages, acquire distinct fate changes. Using mathematical modeling we predict that targeting of the autocrine signal for myofibroblast division could block cold fibrosis. We identify TIMP1 as an autocrine cardiac myofibroblast growth factor in-vitro. Treatment of adult mice after MI with anti-TIMP1 antibodies reduces fibrosis in-vivo. This study shows the utility of the concepts of hot and cold fibrosis and the feasibility of our circuit-to-target approach to reduce fibrosis after acute cardiac injury by inhibiting the myofibroblast autocrine loop.

systems biology↗

bioRxiv2022

Redifferentiated cardiomyocytes retain residual dedifferentiation signatures and are protected against ischaemic injury

Cardiomyocyte renewal by dedifferentiation and proliferation has fueled the field of regenerative cardiology in recent years, while the reverse process of redifferentiation remains largely unexplored. Redifferentiation is characterised by the restoration of function that is lost during dedifferentiation and is key to the healing process following injury. Previously, we showed that ERBB2-mediated heart regeneration has these two distinct phases: dedifferentiation, followed by redifferentiation. Here, using temporal RNAseq and proteomics, we survey the landscape of the dedifferentiation-redifferentiation process in the adult mouse heart. We find well characterised dedifferentiation pathways, such as reduced oxphos, increased proliferation and increased EMT-like features, largely return to normal, though elements of residual dedifferentiation remain, even after contractile function is restored. These hearts appeared rejuvenated and showed robust resistance to ischaemic injury. We find that redifferentiation is driven by negative feedback signalling, notably through LATS1/2 Hippo pathway activity. Disabling LATS1/2 in dedifferentiated cardiomyocytes augments dedifferentiation in vitro and prevents redifferentiation in vivo. Taken together, our data reveal the non-trivial nature of redifferentiation, whereby elements of dedifferentiation linger in a surprisingly beneficial manner. This cycle of dedifferentiation-redifferentiation protects against future insult, in what could become a novel prophylactic treatment against ischemic heart disease for at-risk patients.

cell biology↗

bioRxiv2020

ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration

Cardiomyocyte (CM) loss after injury results in adverse remodelling and fibrosis, which inevitably lead to heart failure. ERBB2-Neuregulin and Hippo-YAP signaling pathways are key mediators of CM proliferation and regeneration, yet the crosstalk between these pathways is unclear. Here, we demonstrate in adult mice that transient over-expression (OE) of activated ERBB2 in CMs promotes cardiac regeneration in a heart failure model. OE CMs present an EMT-like regenerative response manifested by cytoskeletal remodelling, junction dissolution, migration, and ECM turnover. Molecularly, we identified YAP as a critical mediator of ERBB2 signaling. In OE CMs, YAP interacts with nuclear envelope and cytoskeletal components, reflecting the altered mechanic state elicited by ERBB2. Hippo-independent activating phosphorylation on YAP at S352 and S274 were enriched in OE CMs, peaking during metaphase, and viral overexpression of YAP phospho-mutants dampened the proliferative competence of OE CMs. Taken together, we demonstrate a potent ERBB2-mediated YAP mechanosensory signaling, involving EMT-like characteristics, resulting in heart regeneration. HighlightsO_LIERBB2-driven regeneration of scarred hearts recapitulates core-EMT processes C_LIO_LIYAP is activated and required downstream to ERBB2 signaling in CMs C_LIO_LIYAP activity is mechanically driven by cytoskeleton and nuclear envelope remodeling C_LIO_LIYAP S274 and S352 phosphorylation is essential for CM mitosis C_LI

molecular biology↗