Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice

Abstract

Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis, hemolytic uremic syndrome, and acute encephalopathies that may lead to sudden death or severe neurologic sequelae. Current treatments, including immunoglobulin G (IgG) immunoadsorption, plasma exchange, steroid pulse therapy, and the monoclonal antibody eculizumab, have limited effects against the severe neurologic sequelae. Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative non-tumorigenic stem cells that naturally reside in the body and are currently under clinical trials for regenerative medicine. When administered intravenously, Musecells accumulate to the damaged tissue, where they exert anti-inflammatory, anti-apoptotic, anti-fibrotic, and immunomodulatory effects, and replace damaged cells by differentiating into tissue-constituent cells. Here, severely immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD-SCID) mice orally inoculated with 9 Â 10 9 colony-forming units of STEC O111 and treated 48 h later with intravenous injection of 5 Â 10 4 Muse cells exhibited 100% survival and no severe after-effects of infection. Suppression of granulocyte-colony-stimulating factor (G-CSF) by RNAi abolished the beneficial effects of Muse cells, leading to a 40% death and significant body weight loss, suggesting the involvement of G-CSF in the beneficial effects of Muse cells in STEC-infected mice. Thus, intravenous administration of Muse cells could be a candidate therapeutic approach for preventing fatal encephalopathy after STEC infection.

Verotoxin Receptor-Based Pathology and Therapies

“…Human Muse cells were used to rescue a NOD-SCID mouse model of EHEC (VT2) induced neurological disease (Ozuru et al, 2019). Forty eight hour after gastrointestinal EHEC treatment Muse cell i.v.…”

Non-Tumorigenic Pluripotent Reparative Muse Cells Provide a New Therapeutic Approach for Neurologic Diseases

“…Muse cell-derived neuronal cells incorporate into the pyramidal tract, including the pyramidal decussation, as demonstrated by anterograde and retrograde tracing, and into the sensory tract, as demonstrated by somatosensory-evoked potentials and the formation of synapses with host neuronal cells at 3 months, leading to statistically meaningful functional recovery [ 34 , 38 ]. Spontaneous differentiation of Muse cells into neuronal and glial cells after homing to the damaged central nervous system is also reported in other models, perinatal hypoxic ischemic encephalopathy, brain hemorrhage, ALS, and STEC-related encephalopathy [ 36 , 37 , 39 , 40 ]. In an acute myocardial infarction model, Muse cells homed to the post-infarct tissue and within 2 weeks spontaneously differentiated into cells positive for cardiomyocyte markers, such as troponin-I, sarcomeric α-actinin, and connexin 43, exhibiting calcium influx and efflux synchronous with heart activity recorded by an electrocardiogram [ 6 ].…”

“…In a rabbit acute myocardial infarction model, ~14.5% of intravenously injected Muse cells engrafted into the post-infarct heart at 3 days, whereas only a few or no MSCs integrated into the heart in the same model [ 6 ] ( Figure 6 ). In mouse models of epidermolysis bullosa [ 33 ], lacunar stroke l [ 34 ], doxorubicin-induced nephropathy [ 35 ], ALS [ 36 ], and Shiga toxin-producing Escherichia coli (STEC)-associated encephalopathy [ 37 ], as well as in rat models of middle cerebral artery occlusion ischemia and perinatal hypoxic ischemic encephalopathy [ 38 , 39 ], Muse cells exhibited superiority over MSCs/non-Muse MSCs in selective homing to the sites of damage. Not only in these animal models, but also the data collected from patients with stroke and acute myocardial infarction demonstrated that an increase in the serum S1P level precedes the increase in the number of circulating endogenous Muse cells after the cell injury onset [ 3 , 7 ].…”

“…With regard to their anti-inflammatory effect, Muse cells actively produce interleukin-10, transforming growth factor-β, and prostaglandin E2 [ 17 , 47 ]. Granulocyte colony stimulating factor production was recently demonstrated to play a central role in the activities of Muse cells to protect the blood–brain barrier and neural cells in STEC-associated encephalopathy [ 37 ].…”

“…These differences between Muse cells and MSCs are considered to arise from the differences in their specific homing abilities, the length of survival in the host tissue after intravenous injection, differentiation potential, and immunomodulation. Unlike Muse cells, MSCs do not home to damaged tissue, nor do they remain in the tissue or the body for more than 2 weeks after administration [ 6 , 27 , 35 , 37 , 39 ]. MSCs differentiate into osteocytes, adipocytes, and chondrocytes with lower efficiency than Muse cells and are unable to differentiate into other mesodermal cells or into ectodermal or endodermal lineage cells [ 26 ].…”