Circulating apoptotic bodies maintain mesenchymal stem cell homeostasis and ameliorate osteopenia via transferring multiple cellular factors

Abstract

In the human body, 50-70 billion cells die every day, resulting in the generation of a large number of apoptotic bodies. However, the detailed biological role of apoptotic bodies in regulating tissue homeostasis remains unclear. In this study, we used Fas-deficient MRL/lpr and Caspase 3 mice to show that reduction of apoptotic body formation significantly impaired the self-renewal and osteo-/adipo-genic differentiation of bone marrow mesenchymal stem cells (MSCs). Systemic infusion of exogenous apoptotic bodies rescued the MSC impairment and also ameliorated the osteopenia phenotype in MRL/lpr, Caspase 3 and ovariectomized (OVX) mice. Mechanistically, we showed that MSCs were able to engulf apoptotic bodies via integrin αvβ3 and reuse apoptotic body-derived ubiquitin ligase RNF146 and miR-328-3p to inhibit Axin1 and thereby activate the Wnt/β-catenin pathway. Moreover, we used a parabiosis mouse model to reveal that apoptotic bodies participated in the circulation to regulate distant MSCs. This study identifies a previously unknown role of apoptotic bodies in maintaining MSC and bone homeostasis in both physiological and pathological contexts and implies the potential use of apoptotic bodies to treat osteoporosis.

Differential effects of heat-inactivated, secretome-deficient MSC and metabolically active MSC in sepsis and allogenic heart transplantation

“…It has also been described that the engulfment of apoptotic cells and apoptotic bodies regulates the immune response and may prime the development of a molecular memory in macrophages . Moreover, it was suggested that circulating apoptotic bodies maintain homeostasis of MSCs . However, HI‐MSCs do not undergo apoptosis .…”

Extracellular Vesicles Derived From Apoptotic Cells: An Essential Link Between Death and Regeneration

“…MicroRNAs enclosed in ApoBDs from cardiomyocytes enhance the proliferation and differentiation of resident SCs in vitro ( Tyukavin et al, 2015 ). Mesenchymal stem cells (MSCs) can engulf ApoBDs and reuse ApoBD-derived ubiquitin ligase RNF146 and miR-328-3p to promote bone regeneration ( Liu et al, 2018 ). However, in Kogianni et al (2008) showed that dying osteocytes release ApoBDs containing receptor activator of nuclear factor kappa-B ligand (RANKL) to recruit replacement osteoclasts, which can initiate osteoclastogenesis and localized bone destruction.…”

“…After phagocytizing ApoBDs, the Wnt signaling is activated to stimulate the division of basal SCs to maintain the total number of basal SCs in the tissue ( Brock et al, 2019 ). ApoBDs activate the Wnt/β-catenin pathway to promote bone marrow mesenchymal stem cell (BMSC) proliferation and osteogenic, and lipogenic differentiation in Fas-deficient MRL/lpr and Caspase 3 –/– mice ( Liu et al, 2018 ). Thus, activating the Wnt pathway via ApoEVs is essential for promoting cell proliferation and differentiation.…”

Manipulated Mesenchymal Stem Cells Applications in Neurodegenerative Diseases

“…Excessive production of them, due to increased apoptosis, can lead to several neurological disorders like Parkinson's and Alzheimer's disease. Visa versa, reduced production of apoptotic bodies, as a result of decreased apoptosis, can lead to autoimmune disease development (118). They are enriched in histones, DNAs and noncoding RNAs and cell organelles are found inside of these extracellular vesicles.…”

“…Research studies on the therapeutic effects of apoptotic bodies are not as abundant as researches on exosomes and microvesicles. It has been shown that formation of apoptotic bodies has a significant role in osteogenic and adipogenic differentiation of bone marrow MSCs and they are involved in bone homeostasis and can be used to treat osteoporosis (118,121).…”