Phagocytosing differentiated cell-fragments is a novel mechanism for controlling somatic stem cell differentiation within a short time frame

Abstract

Stem cells undergo cytokine-driven differentiation, but this process often takes longer than several weeks to complete. A novel mechanism for somatic stem cell differentiation via phagocytosing ‘model cells’ (apoptotic differentiated cells) was found to require only a short time frame. Pluripotent-like Muse cells, multipotent mesenchymal stem cells (MSCs), and neural stem cells (NSCs) phagocytosed apoptotic differentiated cells via different phagocytic receptor subsets than macrophages. The phagocytosed-differentiated cell-derived contents (e.g., transcription factors) were quickly released into the cytoplasm, translocated into the nucleus, and bound to promoter regions of the stem cell genomes. Within 24 ~ 36 h, the cells expressed lineage-specific markers corresponding to the phagocytosed-differentiated cells, both in vitro and in vivo. At 1 week, the gene expression profiles were similar to those of the authentic differentiated cells and expressed functional markers. Differentiation was limited to the inherent potential of each cell line: triploblastic-, adipogenic-/chondrogenic-, and neural-lineages in Muse cells, MSCs, and NSCs, respectively. Disruption of phagocytosis, either by phagocytic receptor inhibition via small interfering RNA or annexin V treatment, impeded differentiation in vitro and in vivo. Together, our findings uncovered a simple mechanism by which differentiation-directing factors are directly transferred to somatic stem cells by phagocytosing apoptotic differentiated cells to trigger their rapid differentiation into the target cell lineage.

Clinical significance of increased levels of endogenous Muse cells in the myocardium of patients with fulminant myocarditis

“…In this manner, Muse cells are suggested to repair damaged tissues. Indeed, Muse cells differentiate into cardiac-lineage cells after phagocytosing apoptotic cardiomyocytes [9]. In a rabbit model of ischemiareperfusion acute myocardial infarction, engrafted intravenously injected exogenous Muse cells spontaneously differentiated into physiologically active cardiomyocytes in vivo, which demonstrated synchronous activity in electrocardiogram recordings as well as calcium in ux and e ux activity revealed by GCaMP GFP-based Ca calmodulin probe uorescence.…”

“…Circulating endogenous or exogenously administered Muse cells selectively accumulate at sites of damage by sensing sphingosine-1-phosphate (S1P), a key mediator of in ammation produced by damaged cells [8]. After homing to the site of damage, Muse cells phagocytose damaged/apoptoticdifferentiated cells, recycle factors such as transcription factors originally functioning in the differentiated cells, and repair the tissue by rapidly differentiating into the same cell type as the damaged/apoptotic cells to replace the damaged cells [9]. In addition to cellular replacement, Muse cells exert pleiotropic effects, such as anti-in ammatory, anti-brotic, and trophic effects, that also support tissue repair [8,10,11].…”

Stem Cell Therapy for Acute/Subacute Ischemic Stroke with a Focus on Intraarterial Stem Cell Transplantation: From Basic Research to Clinical Trials

“…Recently, a new mechanism of action of replacement by stem cells has been reported. Although stem cells that migrate into ischemic lesions transdifferentiate into various cell lineages by the paracrine effect, MUSE cells, in fact, phagocytose the apoptotic differentiated cells and thereby become differentiated [111]. Thus, stem cells replace the differentiated cells by the paracrine effect or by phagocytosing apoptotic differentiated cells.…”

Structural reconstruction of mouse acute aortic dissection by intravenously administrated human-Muse cells without immunosuppression

“…Therefore, intravenous drip is the main delivery method for clinical application and surgical operation is not required in many cases. Following engraftment in damaged tissue, Muse cells phagocytose damaged cells, recycle signals and factors derived from damaged cells, and differentiate into the same cell type as the damaged cells in a short time period to replace damaged/apoptotic cells and repair the tissue 30 . Therefore, Muse cells do not require gene induction or differentiation manipulation prior to clinical use.…”