Leitner Lucia, Schultheis Martina, Hofstetter Franziska, Rudolf Claudia, Fuchs Christiane, Kizner Valeria, Fiedler Kerstin, Konrad Marie-Therese, Höbaus Julia, Genini Marco, Kober Julia, Ableitner Elisabeth, Gmaschitz Teresa, Walder Diana, Weitzer Georg
Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria; Medical University of Vienna, Center for Medical Biochemistry, Department of Molecular Biology, Vienna, Austria.
Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria; Medical University of Vienna, Center for Medical Biochemistry, Department of Molecular Biology, Vienna, Austria; Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA; Department of Dermatology, Harvard Medical School, Boston, MA, USA.
Cells Dev. 2025 Mar;181:203990. doi: 10.1016/j.cdev.2024.203990. Epub 2024 Dec 27.
The mammalian heart contains cardiac stem cells throughout life, but it has not been possible to harness or stimulate these cells to repair damaged myocardium in vivo. Assuming physiological relevance of these cells, which have evolved and have been maintained throughout mammalian evolution, we hypothesize that cardiac stem cells may contribute to cardiomyogenesis in an unorthodox manner. Since the intermediate filament protein desmin and the matricellular Secreted Protein Acidic and Rich in Cysteine (SPARC) promote cardiomyogenic differentiation during embryogenesis in a cell-autonomous and paracrine manner, respectively, we focus on their genes and employ mouse embryonic and cardiac stem cell lines as in vitro models to ask whether desmin and SPARC cooperatively influence cardiomyogenesis in cardiac stem and progenitor cells. We show that desmin also promotes cardiomyogenesis in a non-cell autonomous manner by increasing the expression and secretion of SPARC in differentiating embryonic stem cells. SPARC is also secreted by cardiac stem cells where it promotes cardiomyogenesis in an autocrine and concentration-dependent manner by upregulating the expression of myocardial transcription factors and its elicitor desmin. Desmin and SPARC interact genetically, forming a positive feedback loop and secreted autocrine and paracrine SPARC negatively affects sparc mRNA expression. Paracrine SPARC rescues cardiomyogenic desmin-haploinsufficiency in cardiac stem cells in a glycosylation-dependent manner, increases desmin expression, the phosphorylation of Smad2 and induces the expression of gata4, nkx2.5 and mef2C. Demonstration that desmin-induced autocrine secretion of SPARC in cardiac stem cells promotes cardiomyogenesis raises the possibility that a physiological function of cardiac stem cells in the adult and aging heart may be the gland-like secretion of factors such as SPARC that modulate age-related and adverse environmental influences and thereby contribute to cardiac homeostasis throughout life.
哺乳动物的心脏在其整个生命过程中都含有心脏干细胞，但在体内利用或刺激这些细胞来修复受损心肌一直是不可能的。鉴于这些在整个哺乳动物进化过程中得以演化并保留下来的细胞具有生理相关性，我们推测心脏干细胞可能以一种非传统的方式促进心肌生成。由于中间丝蛋白结蛋白和基质细胞分泌的富含半胱氨酸的酸性蛋白（SPARC）分别以细胞自主和旁分泌的方式在胚胎发育过程中促进心肌分化，我们聚焦于它们的基因，并采用小鼠胚胎干细胞系和心脏干细胞系作为体外模型，以探究结蛋白和SPARC是否协同影响心脏干细胞和祖细胞的心肌生成。我们发现，结蛋白还通过增加分化中的胚胎干细胞中SPARC的表达和分泌，以非细胞自主的方式促进心肌生成。心脏干细胞也会分泌SPARC，在其中它通过上调心肌转录因子及其诱导剂结蛋白的表达，以自分泌和浓度依赖的方式促进心肌生成。结蛋白和SPARC在基因层面相互作用，形成一个正反馈回路，而分泌的自分泌和旁分泌SPARC会对sparc mRNA表达产生负面影响。旁分泌的SPARC以糖基化依赖的方式挽救心脏干细胞中导致心肌生成的结蛋白单倍剂量不足，增加结蛋白表达、Smad2的磷酸化，并诱导gata4、nkx2.5和mef2C的表达。心脏干细胞中结蛋白诱导的SPARC自分泌分泌促进心肌生成这一发现，增加了一种可能性，即成年和衰老心脏中心脏干细胞的生理功能可能是像腺体一样分泌诸如SPARC之类的因子，这些因子可调节与年龄相关的和不利的环境影响，从而在整个生命过程中维持心脏的稳态。
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