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Parts of this research were filed for a patent application entitled "Method and medium for cultivating animal cells".

Introduction: Adult human stem- and progenitor cells play a crucial role in tissue and organ repair, making them promising candidates for regenerative medicine. However, age-related diseases are often accompanied by a decline in endogenous stem cell-based regeneration. Blood serum has shown rejuvenating effects in animal studies, but its translation to human the system requires further elucidation of underlying molecular mechanisms. Further, a deeper understanding of stem cell proliferation at the molecular level is necessary to address age-related diseases and expand stem cell therapies. We here investigated the proliferative effects of human blood serum on adult human cardiac stem cells with a special focus on cell-type specific TFGβ signaling.

Methods: Human cardiac stem cells (hCSCs) were treated with human blood serum and selective inhibitors for the TGFβ receptors TGFβRI and TGFβRII. Proliferation- and senescence assays served as functional outread. RNAseq was applied to gain a deeper insight into the molecular regulation of hCSC proliferation.

Results: RNA-Seq of serum-treated hCSCs indicated the involvement of TGFβ signaling in regulating key mechanisms of cellular proliferation. Functional assays confirmed TGFβ as a major mediator of serum-induced effects in hCSCs. The application of human blood serum as well as of TGFβ1 resulted in increased proliferation and protection from senescence in hCSCs. Inhibition of this pathway showed that TGFβRI inhibition reduces serum-mediated proliferation, while the inhibition of both receptors, TGFβRI and TGFβRII, strongly increased hCSC proliferation.

Conclusion: Our data indicate TGFβ signaling playing a dual role in the serum-mediated effects on hCSCs, crucial for their proliferation and senescence regulation. These findings enhance our understanding of the molecular basis of serum-mediated hCSC proliferation and senescence, contributing to potential advancements in regenerative medicine to treat age-related cardiovascular diseases. Further research into these pathways could improve therapeutic strategies for heart failure and other related conditions.