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

Abstract

Posttransplantation lung ischemia–reperfusion (IR) injuries affect both patient survival and graft function. In this study, we evaluated the protective effects of infused human multilineage-differentiating stress-enduring (Muse) cells, a novel, easily harvested type of nontumorigenic endogenous reparative stem cell, against acute IR lung injury in a rat model. After a 2-h warm IR injury induction in a left rat lung, human Muse cells, human mesenchymal stem cells (MSCs), and vehicle were injected via the left pulmonary artery after reperfusion. Functionality, histological findings, and protein expression were subsequently assessed in the injured lung. In vitro, we also compared human Muse cells with human MSCs in terms of migration abilities and the secretory properties of protective substances. The arterial oxygen partial pressure to fractional inspired oxygen ratio, alveolar-arterial oxygen gradient, left lung compliance, and histological injury score on hematoxylin–eosin sections were significantly better in the Muse group relative to the MSC and vehicle groups. Compared to MSCs, human Muse cells homed more efficiently to the injured lung, where they suppressed the apoptosis and stimulated proliferation of host alveolar cells. Human Muse cells also migrated to serum from lung-injured model rats and produced beneficial substances (keratinocyte growth factor [KGF], hepatocyte growth factor, angiopoietin-1, and prostaglandin E2) in vitro. Western blot of lung tissue confirmed high expression of KGF and their target molecules (interleukin-6, protein kinase B, and B-cell lymphoma-2) in the Muse group. Thus, Muse cells efficiently ameliorated lung IR injury via pleiotropic effects in a rat model. These findings support further investigation on the use of human Muse cells for lung IR injury.

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 – 19 , 31 . Therefore, they might have supplied beneficial factors to motor neurons and astrocytes, preventing myofiber atrophy in the ALS model.…”

“…Muse cells are unique for several reasons: they recognize damaged tissue and selectively accumulate at the site of damage by intravenous injection because they express sphingosine-1-phosphate (S1P) receptor 2, which recognizes the S1P produced by damaged/apoptotic cells; after homing to the damaged site, Muse cells replace damaged/apoptotic cells by spontaneous differentiation into the damaged/apoptotic cell-type, and contribute to tissue repair, as shown by animal models of stroke, acute myocardial infarction, epidermolysis bullosa, chronic kidney disease and liver cirrhosis 14 – 18 . Besides their effects on tissue repair, Muse cells have pleiotropic effects including neovascularization, immunomodulation, trophic-, anti-apoptotic-, and anti-fibrotic effects 18 , 19 . Another important and unique feature is that allogeneic-Muse cells escape host immunorejection after intravenous administration and survive in the host tissue as differentiated cells for over 6 months, even without immunosuppressive treatment 18 .…”

Quantitative Analysis of SSEA3+ Cells from Human Umbilical Cord after Magnetic Sorting

“…Although HUC-derived SSEA3þ and CD105þ cells form neural spheres (ectodermal), we did not observe induction into endodermal or mesodermal cells. However, past studies have shown that HUC-derived SSEA3þ and CD105þ cells can differentiate into the three lineages [63][64][65][66][67] .…”

Muse cells and Neurorestoratology

“…Corresponding author: Xijing He, E-mail: xijing_h@vip.tom.com induction factors in different specific media in vitro, 98% of cells were Osteocalcin+ (osteocyte, mesoderm) [2], 98% were red oil+ (adipocyte, mesoderm) [2], 90% were α-FP+ (hepatocyte, entoderm) [2], 90% were MAP-2+ (Neuron, ectoderm) [2], and 43.1 ± 17.1% were GP100+ (melanocyte, ectoderm) [7,8]. When induced Muse cell cultures were transplanted in vivo, cells differentiated into adipocytes, skeletal muscle cells, myocardial cells, biliary epithelial cells, glomerular cells, glomerular endothelial cells, melanocytes and neurons [8][9][10][11][12][13][14][15][16].…”