Ablation of a Single N-Glycosylation Site in Human FSTL 1 Induces Cardiomyocyte Proliferation and Cardiac Regeneration

Magadum, Ajit; Singh, Neha; Kurian, Achamma; Sharkar, Mohammad Tofael Kabir; Chepurko, Elena; Zangi, Lior

doi:10.1016/j.omtn.2018.08.021

Cited by 59 publications

(57 citation statements)

References 43 publications

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“…The biological function of FSTL1 is closely related to its posttranslational modification by N-linked glycosylation [36,37]. Consistent with the enrichment of the glycosylated FSTL1 in BAT (Fig.…”

Section: Glycosylation Was Essential For the Biological Function Of Fsupporting

confidence: 79%

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The glycoprotein follistatin-like 1 promotes brown adipose thermogenesis

Fang

et al. 2019

Metabolism

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The thermogenic brown adipose tissue (BAT) has been proposed as a potential target to prevent or treat obesity and related metabolic diseases. BAT secretes adipokines to regulate the thermogenic program in an autocrine or paracrine manner. Follistatin-like 1 (FSTL1), a glycoprotein involved in adipogenesis and obesity, however, the function of FSTL1 in BAT thermogenesis and in the regulation of systemic energy homeostasis are not fully understood. Methods: Whole-body ablation Fstl1 heterozygous mice (Fstl1 +/−) and its littermates control were injected with CL316,243 to assess energy balance. A series of FSTL1 overexpression and knockdown experiments were carried out to evaluate its function in regulating thermogenic gene expression in brown adipocytes. Results: FSTL1 expression was induced upon BAT activation during cold challenge or β3-adrenergic activation. FSTL1 haploinsufficiency in mice led to reduced thermogenic gene expression, impaired BAT recruitment, and decreased heat production. FSTL1 cell-autonomously promoted the β3-adrenergic signaling, which was required to upregulate PPARγ and UCP1 in brown adipocytes. Furthermore, only glycosylated FSTL1 could be secreted from brown adipocytes to induce the β3-adrenergic activation. Conclusions: Our results suggest FSTL1 as a novel stimulator of the β-adrenergic signaling and BAT thermogenesis.

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Section: Glycosylation Was Essential For the Biological Function Of Fsupporting

confidence: 79%

“…In mouse FSTL1, three potential sites for N-glycosylation and two for O-glycosylation are present. An in vitro study has shown that only the three aspartate residues Asp 142 , Asp 173 , and Asp 178 are Nglycosylated and show cell-type specificity [36]. In our study, we found that FSTL1 in brown fat cells is highly glycosylated.…”

Section: Discussionsupporting

confidence: 60%

The glycoprotein follistatin-like 1 promotes brown adipose thermogenesis

Fang

et al. 2019

Metabolism

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“…Collectively, our data are primary in linking, within a human model, the benefit of allogeneic stem/progenitor-based therapy to the activity of EV/Exs secreted by therapeutic cells. Resident cardiac stem/progenitor cells and cardiomyocytes are critical not only for tissue homeostasis and renewal of cardiomyocyte pool [39], but also for organ regeneration and/or repair after cardiac injury [40][41][42]. The rapid internalization of EV/Exs by allogeneic hCPC and cardiomyocytes, which represented in situ resident myocytes in our in vitro model, promoted both migration and proliferation.…”

Section: Discussionmentioning

confidence: 92%

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

Hocine

Brunel

Chen

et al. 2019

Stem Cells Translational Medicine

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The positive effects of therapeutic human allogeneic cardiac stem/progenitor cells (hCPC) in terms of cardiac repair/regeneration are very likely mediated by paracrine effects. Our previous studies revealed the advantageous immune interactions of allogeneic hCPC and proposed them as part of the positive paracrine effects occurring upon their application postmyocardial infarction (MI). Currently, extracellular vesicles/exosomes (EV/Exs) released by stem/progenitor cells are also proposed as major mediators of paracrine effects of therapeutic cells. Along this line, we evaluated contribution of EV/Exs released by therapeutic hCPC to the benefit of their successful allogeneic clinical application. Through tailored allogeneic in vitro human assay models mimicking the clinical setting, we demonstrate that hCPC‐released EV/Exs were rapidly and efficiently up‐taken by chief cellular actors of cardiac repair/regeneration. This promoted MAPK/Erk1/2 activation, migration, and proliferation of human leukocyte antigens (HLA)‐mismatched hCPC, mimicking endogenous progenitor cells and cardiomyocytes, and enhanced endothelial cell migration, growth, and organization into tube‐like structures through activation of several signaling pathways. EV/Exs also acted as pro‐survival stimuli for HLA‐mismatched monocytes tuning their phenotype toward an intermediate anti‐inflammatory pro‐angiogenic phenotype. Thus, while positively impacting the intrinsic regenerative and angiogenic programs, EV/Exs released by therapeutic allogeneic hCPC can also actively contribute to shaping MI‐inflammatory environment, which could strengthen the benefits of hCPC allogeneic interactions. Collectively, our data might forecast the application of allogeneic hCPC followed by their cell‐free EV/Exs as a strategy that will not only elicit the cell‐contact mediated reparative/regenerative immune response but also have the desired long‐lasting effects through the EV/Exs. stem cells translational medicine 2019;8:911&924

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“… 57 EGFP, mCherry, Fluc modRNA delivery optimization optimal modRNA expression in heart alginate, nanomaterial encapsulated mice and pig 11 Magadum et al. 48 mutated FSTL1 ablation of N180Q, N-glycosylation site of hFSTL1 by modRNA delivery increased CM proliferation, improved cardiac output, and reduced scar size post-MI CM proliferation, decreased scar size, improved heart function sucrose-citrate buffer mice …”

Section: Main Textmentioning

confidence: 99%

mRNA-Based Protein Replacement Therapy for the Heart

2019

Self Cite

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Myocardial infarction (MI) and heart failure (HF) are the leading causes of death in the United States and in most other industrialized nations. MI leads to a massive loss of cardiomyocytes (CMs), which are replaced with non-CM cells, leading to scarring and, in most cases, HF. The adult mammalian heart has a low intrinsic regenerative capacity, mainly because of cell-cycle arrest in CMs. No effective treatment promoting heart regeneration is currently available. Recent efforts to use DNA-based or viral gene therapy approaches to induce cardiac regeneration post-MI or in HF conditions have encountered major challenges, mostly because of the poor and uncontrolled delivery of the introduced genes. Modified mRNA (modRNA) is a safe, non-immunogenic, efficient, transient, local, and controlled nucleic acid delivery system that can overcome the obstacles to DNA-based or viral approaches for cardiac gene delivery. We here review the use of modRNA in cardiac therapy, to induce cardioprotection and vascular or cardiac regeneration after MI. We discuss the current challenges in modRNA-based cardiac treatment, which will need to be overcome for the application of such treatment to ischemic heart disease.

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Ablation of a Single N-Glycosylation Site in Human FSTL 1 Induces Cardiomyocyte Proliferation and Cardiac Regeneration

Cited by 59 publications

References 43 publications

The glycoprotein follistatin-like 1 promotes brown adipose thermogenesis

The glycoprotein follistatin-like 1 promotes brown adipose thermogenesis

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

mRNA-Based Protein Replacement Therapy for the Heart

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