The Role of Blood-Derived Factors in Protection and Regeneration of Aged Tissues

Hoving AL, Schmidt KE, Kaltschmidt B, Kaltschmidt C, Knabbe C. The Role of Blood-Derived Factors in Protection and Regeneration of Aged Tissues. International Journal of Molecular Sciences. 2022;23(17): 9626.Tissue regeneration substantially relies on the functionality of tissue-resident endogenous adult stem cell populations. However, during aging, a progressive decline in organ function and regenerative capacities impedes endogenous repair processes. Especially the adult human heart is considered as an organ with generally low regenerative capacities. Interestingly, beneficial effects of systemic factors carried by young blood have been described in diverse organs including the heart, brain and skeletal muscle of the murine system. Thus, the interest in young blood or blood components as potential therapeutic agents to target age-associated malignancies led to a wide range of preclinical and clinical research. However, the translation of promising results from the murine to the human system remains difficult. Likewise, the establishment of adequate cellular models could help to study the effects of human blood plasma on the regeneration of human tissues and particularly the heart. Facing this challenge, this review describes the current knowledge of blood plasma-mediated protection and regeneration of aging tissues. The current status of preclinical and clinical research examining blood borne factors that act in stem cell-based tissue maintenance and regeneration is summarized. Further, examples of cellular model systems for a more detailed examination of selected regulatory pathways are presented

Serum-Induced Proliferation of Human Cardiac Stem Cells Is Modulated via TGFβRI/II and SMAD2/3

Schmidt KE, Höving AL, Kiani Zahrani S, et al. Serum-Induced Proliferation of Human Cardiac Stem Cells Is Modulated via TGFβRI/II and SMAD2/3. International Journal of Molecular Sciences. 2024;25(2): 959.The ageing phenotype is strongly driven by the exhaustion of adult stem cells (ASCs) and the accumulation of senescent cells. Cardiovascular diseases (CVDs) and heart failure (HF) are strongly linked to the ageing phenotype and are the leading cause of death. As the human heart is considered as an organ with low regenerative capacity, treatments targeting the rejuvenation of human cardiac stem cells (hCSCs) are of great interest. In this study, the beneficial effects of human blood serum on proliferation and senescence of hCSCs have been investigated at the molecular level. We show the induction of a proliferation-related gene expression response by human blood serum at the mRNA level. The concurrent differential expression of the TGFβ target and inhibitor genes indicates the participation of TGFβ signalling in this context. Surprisingly, the application of TGFβ1 as well as the inhibition of TGFβ type I and type II receptor (TGFβRI/II) signalling strongly increased the proliferation of hCSCs. Likewise, both human blood serum and TGFβ1 reduced the senescence in hCSCs. The protective effect of serum on senescence in hCSCs was enhanced by simultaneous TGFβRI/II inhibition. These results strongly indicate a dual role of TGFβ signalling in terms of the serum-mediated effects on hCSCs. Further analysis via RNA sequencing (RNA-Seq) revealed the participation of Ras-inactivating genes wherefore a prevention of hyperproliferation upon serum-treatment in hCSCs via TGFβ signalling and Ras-induced senescence is suggested. These insights may improve treatments of heart failure in the future

Human Blood Serum Induces p38-MAPK- and Hsp27-Dependent Migration Dynamics of Adult Human Cardiac Stem Cells: Single-Cell Analysis via a Microfluidic-Based Cultivation Platform

Schmitz J, Höving AL, Schmidt KE, et al. Human Blood Serum Induces p38-MAPK- and Hsp27-Dependent Migration Dynamics of Adult Human Cardiac Stem Cells: Single-Cell Analysis via a Microfluidic-Based Cultivation Platform. Biology. 2021;10(8): 708.Migratory capabilities of adult human stem cells are vital for assuring endogenous tissue regeneration and stem cell-based clinical applications. Although human blood serum has been shown to be beneficial for cell migration and proliferation, little is known about its impact on the migratory behavior of cardiac stem cells and underlying signaling pathways. Within this study, we investigated the effects of human blood serum on primary human cardiac stem cells (hCSCs) from the adult heart auricle. On a technical level, we took advantage of a microfluidic cultivation platform, which allowed us to characterize cell morphologies and track migration of single hCSCs via live cell imaging over a period of up to 48 h. Our findings showed a significantly increased migration distance and speed of hCSCs after treatment with human serum compared to control. Exposure of blood serum-stimulated hCSCs to the p38 mitogen-activated protein kinase (p38-MAPK) inhibitor SB239063 resulted in significantly decreased migration. Moreover, we revealed increased phosphorylation of heat shock protein 27 (Hsp27) upon serum treatment, which was diminished by p38-MAPK-inhibition. In summary, we demonstrate human blood serum as a strong inducer of adult human cardiac stem cell migration dependent on p38-MAPK/Hsp27-signalling. Our findings further emphasize the great potential of microfluidic cultivation devices for assessing spatio-temporal migration dynamics of adult human stem cells on a single-cell level

Blood Serum Stimulates p38-Mediated Proliferation and Changes in Global Gene Expression of Adult Human Cardiac Stem Cells

Höving AL, Schmidt KE, Merten M, et al. Blood Serum Stimulates p38-Mediated Proliferation and Changes in Global Gene Expression of Adult Human Cardiac Stem Cells. Cells. 2020;9(6): 1472.During aging, senescent cells accumulate in various tissues accompanied by decreased regenerative capacities of quiescent stem cells, resulting in deteriorated organ function and overall degeneration. In this regard, the adult human heart with a generally low regenerative potential is of extreme interest as a target for rejuvenating strategies with blood borne factors that might be able to activate endogenous stem cell populations. Here, we investigated for the first time the effects of human blood plasma and serum on adult human cardiac stem cells (hCSCs) and showed significantly increased proliferation capacities and metabolism accompanied by a significant decrease of senescent cells, demonstrating a beneficial serum-mediated effect that seemed to be independent of age and sex. However, RNA-seq analysis of serum-treated hCSCs revealed profound effects on gene expression depending on the age and sex of the plasma donor. We further successfully identified key pathways that are affected by serum treatment with p38-MAPK playing a regulatory role in protection from senescence and in the promotion of proliferation in a serum-dependent manner. Inhibition of p38-MAPK resulted in a decline of these serum-mediated beneficial effects on hCSCs in terms of decreased proliferation and accelerated senescence. In summary, we provide new insights in the regulatory networks behind serum-mediated protective effects on adult human cardiac stem cells

Serum Induces the Subunit-Specific Activation of NF-κB in Proliferating Human Cardiac Stem Cells

Schmidt KE, Höving AL, Nowak K, et al. Serum Induces the Subunit-Specific Activation of NF-κB in Proliferating Human Cardiac Stem Cells. International Journal of Molecular Sciences. 2024;25(7): 3593.Cardiovascular diseases (CVDs) are often linked to ageing and are the major cause of death worldwide. The declined proliferation of adult stem cells in the heart often impedes its regenerative potential. Thus, an investigation of the proliferative potential of adult human cardiac stem cells (hCSCs) might be of great interest for improving cell-based treatments of cardiovascular diseases. The application of human blood serum was already shown to enhance hCSC proliferation and reduce senescence. Here, the underlying signalling pathways of serum-mediated hCSC proliferation were studied. We are the first to demonstrate the involvement of the transcription factor NF-κB in the serum-mediated proliferative response of hCSCs by utilizing the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC). RNA-Sequencing (RNA-Seq) revealed ATF6B, COX5B, and TNFRSF14 as potential targets of NF-κB that are involved in serum-induced hCSC proliferation

Blood serum stimulates p38-mediated proliferation and changes in global gene expression of adult human cardiac stem cells

During aging, senescent cells accumulate in various tissues accompanied by decreased regenerative capacities of quiescent stem cells, resulting in deteriorated organ function and overall degeneration. In this regard, the adult human heart with a generally low regenerative potential is of extreme interest as a target for rejuvenating strategies with blood borne factors that might be able to activate endogenous stem cell populations. Here, we investigated for the first time the effects of human blood plasma and serum on adult human cardiac stem cells (hCSCs) and showed significantly increased proliferation capacities and metabolism accompanied by a significant decrease of senescent cells, demonstrating a beneficial serum-mediated effect that seemed to be independent of age and sex. However, RNA-seq analysis of serum-treated hCSCs revealed profound effects on gene expression depending on the age and sex of the plasma donor. We further successfully identified key pathways that are affected by serum treatment with p38-MAPK playing a regulatory role in protection from senescence and in the promotion of proliferation in a serum-dependent manner. Inhibition of p38-MAPK resulted in a decline of these serum-mediated beneficial effects on hCSCs in terms of decreased proliferation and accelerated senescence. In summary, we provide new insights in the regulatory networks behind serum-mediated protective effects on adult human cardiac stem cells

Global changes in the nuclear positioning of genes and intra- and interdomain genomic interactions that orchestrate B cell fate

The genome is folded into domains located in either transcriptionally inert or permissive compartments. Here we used genome-wide strategies to characterize domains during B cell development. Structured Interaction Matrix Analysis revealed that CTCF occupancy was primarily associated with intra-domain interactions, whereas p300, E2A and PU.1 bound sites were associated with intra- and inter-domain interactions that are developmentally regulated. We identified a spectrum of genes that switched nuclear location during early B cell development. In progenitors the transcriptionally inactive Ebf1 locus was sequestered at the nuclear lamina, thereby preserving multipotency. Upon development into the pro-B cell stage Ebf1 and other genes switched compartments to establish de novo intra- and inter-domain interactions that are associated with a B lineage specific transcription signature