Beneficial Effects of Systemically Administered Human Muse Cells in Adriamycin Nephropathy

Abstract

Multilineage-differentiating stress-enduring (Muse) cells are nontumorigenic endogenous pluripotent-like stem cells that can be collected from various organs. Intravenously administered Muse cells have been shown to spontaneously migrate to damaged tissue and replenish lost cells, but the effect in FSGS is unknown. We systemically administered human bone marrow-derived Muse cells without concurrent administration of immunosuppressants to severe combined immune-deficient (SCID) and BALB/c mouse models with adriamycin-induced FSGS (FSGS-SCID and FSGS-BALB/c, respectively). In FSGS-SCID mice, human Muse cells preferentially integrated into the damaged glomeruli and spontaneously differentiated into cells expressing markers of podocytes (podocin; 31%), mesangial cells (megsin; 13%), and endothelial cells (CD31; 41%) without fusing to the host cells; attenuated glomerular sclerosis and interstitial fibrosis; and induced the recovery of creatinine clearance at 7 weeks. Human Muse cells induced similar effects in FSGS-BALB/c mice at 5 weeks, despite xenotransplant without concurrent immunosuppressant administration, and led to improvement in urine protein, creatinine clearance, and plasma creatinine levels more impressive than that in the FSGS-SCID mice at 5 weeks. However, functional recovery in FSGS-BALB/c mice was impaired at 7 weeks due to immunorejection, suggesting the importance of Muse cell survival as glomerular cells in the FSGS kidney for tissue repair and functional recovery. In conclusion, Muse cells are unique reparative stem cells that preferentially home to damaged glomeruli and spontaneously differentiate into glomerular cells after systemic administration. Introduction of genes to induce differentiation is not required before Muse cell administration; thus, Muse cells may be a feasible therapeutic strategy in FSGS.

Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis

“…Reactive astrocytes are an important therapeutic target of ALS 29 , and the microenvironmental signal of the ALS mice spinal cord may differentiate Muse cells into GFAP-positive astrocytes, especially into A2 astrocytes, which might secrete molecules that provide neurotrophic support and modulate inflammatory responses 30 . Muse cells themselves can produce various neurotrophic factors, including brain-derived neurotrophic factor (BDNF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1), epidermal growth factor (EGF), prostaglandin E2 (PGE2), and angiopietin-1 (Ang1) [16][17][18][19]31 . Therefore, they might have supplied beneficial factors to motor neurons and astrocytes, preventing myofiber atrophy in the ALS model.…”

Regeneration of pulpo-dentinal–like complex by a group of unique multipotent CD24a + stem cells

“…Muse cells (multilineage differentiating stress enduring cells) are a group of multipotent stem cells identified from 3D culture of bone marrow stromal cells that could be differentiated into multiple lineages in vitro and in vivo (20). Although it is still highly controversial due to the lack of in vivo identities (21), the isolation (21) and application of muse cells in animal disease models are well documented from multiple laboratories (22)(23)(24). These evidences indicated that the 3D culture system used in muse cells identification might be stromal stem cell supportive, which makes it attractive to use in our primary DPC culture to test whether there are previous undocumented stem cells in dental papilla.…”

Human Multilineage-differentiating Stress-Enduring Cells Exert Pleiotropic Effects to Ameliorate Acute Lung Ischemia–Reperfusion Injury in a Rat Model

“…Regarding feasibility for clinical applications, an approximately 30 mL volume of human bone marrow (BM) aspirate yields 1 million Muse cells by day 3 7 . In recent studies involving animal models of muscle damage 8 , stroke 13 , liver damage 14 , 15 , and chronic kidney disease 16 , intravenously or locally injected Muse cells actively migrated to and preferentially engrafted into damaged tissues, spontaneously differentiated into tissue-compatible cells in response to the microenvironment, and facilitated structural and functional recovery 8 . Recent publications also reported that the trophic effects of Muse cells facilitated tissue repair in animal models of diabetes mellitus–related skin ulcers 17 , 18 .…”