Behavior of Xeno-Transplanted Undifferentiated Human Induced Pluripotent Stem Cells Is Impacted by Microenvironment Without Evidence of Tumors

Abstract

Human pluripotent stem cells (hPSC) have great clinical potential through the use of their differentiated progeny, a population in which there is some concern over risks of tumorigenicity or other unwanted cellular behavior due to residual hPSC. Preclinical studies using human stem cells are most often performed within a xenotransplant context. In this study, we sought to measure how undifferentiated hPSC behave following xenotransplant. We directly transplanted undifferentiated human induced pluripotent stem cells (hIPSC) and human embryonic stem cells (hESC) into the adult mouse brain ventricle and analyzed their fates. No tumors or precancerous lesions were present at more than one year after transplantation. This result differed with the tumorigenic capacity we observed after allotransplantation of mouse ESC into the mouse brain. A substantial population of cellular derivatives of undifferentiated hESC and hIPSC engrafted, survived, and migrated within the mouse brain parenchyma. Within brain structures, transplanted cell distribution followed a very specific pattern, suggesting the existence of distinct microenvironments that offer different degrees of permissibility for engraftment. Most of the transplanted hESC and hIPSC that developed into brain cells were NeuN+ neuronal cells, and no astrocytes were detected. Substantial cell and nuclear fusion occurred between host and transplanted cells, a phenomenon influenced by microenvironment. Overall, hIPSC appear to be largely functionally equivalent to hESC in vivo. Altogether, these data bring new insights into the behavior of stem cells without prior differentiation following xenotransplantation into the adult brain.

Transfer of nuclear and ribosomal material from Sox10-lineage cells to neurons in the mouse brain

“…The presence of vesicles and free ribosomes in the SOL-neuron internuclear space suggests that material can be transferred directly between nuclei without passing the plasma membrane. Fusion and donation of genetic material to neurons have been reported in the mouse and human brain after stem cell transplantation and are especially common between cerebellar Purkinje neurons ( Alvarez-Dolado et al, 2003 ; Martínez-Cerdeño et al, 2017 ; Weimann et al, 2003a ; Weimann et al, 2003b ). However, strict confinement of SOL-specific proteins to SOL and specificity of Cre and reporter protein expression to SOL argues against complete cell fusion and supports the concept of selective SOL-neuron material transfer.…”

Recent advances for using human induced-pluripotent stem cells as pain-in-a-dish models of neuropathic pain

“…signaling cues necessary for sensory neurons to express their full proteome range (Martinez-Cerdeno et al, 2017), by analogy to an in vivo differentiated iPSC-derived cardiomyocyte model, where xenotransplanted cells acquired additional protein markers, at similar levels to native cardiac cells (Yu et al, 2013).…”

Developmental Changes of Human Neural Progenitor Cells Grafted into the Ventricular System and Prefrontal Cortex of Mouse Brain in Utero

“…A large number of pre-clinical studies have already demonstrated the capacity for neuronal transplants to integrate within rodent brains and respond to guiding molecules and signals, under in vivo conditions [ 3 , 4 ]. In addition, it has been shown that transplanted pyramidal neurons derived from human embryonic stem cells can be specifically directed toward their appropriate sites of differentiation and maturation [ 5 , 6 ]. So far, the neuronal xenotransplants which have been obtained from hiPSCs include human neurospheres [ 7 ], human neuronal progenitor cells (hNPCs) [ 8 , 9 ], purified hiPSC-derived neurons with defined phenotypes [ 5 , 10 ], and, more recently, human brain organoids [ 11 , 12 , 13 ].…”