Induced Pluripotent Stem Cells Can Effectively Differentiate into Multiple Functional Lymphocyte Lineages In Vivo with Negligible Bias

Abstract

Lymphohematopoietic stem cells (L-HSCs) generated from self-somatic cell-derived induced pluripotent stem cells (iPSCs) are a potential source of cells for the treatment of hematological disorders. However, the generation of truly functional L-HSCs from iPSCs has yet to be achieved. Thus, whether iPSCs have the inherent potential to generate a normal differentiated phenotype and functional population of multiple lineages of terminally differentiated lymphocytes needs to be assessed. Here, we used tetraploid embryo complementation to provide a normal environment for the differentiation of hematopoietic cells from iPSCs and embryonic stem cells (ESCs). We then evaluated the characteristics, populations, and functions of lymphocytes derived from iPSCs, ESCs, and naïve isogenic C57BL/6 mice. The results showed that iPSC-derived lymphocytes (iPSLs) expressed normal levels of major histocompatibility complex-I (MHC-I) and exhibited a fully pluripotent capacity to differentiate into CD4(+) T, CD8(+) T, regulatory T, B, and natural killer cells. Following in vitro stimulation with either concanavalin A or an alloantigen, iPSLs exhibited the same capacities for proliferation and cytokine secretion as ESC-derived or isogenic lymphocytes. Furthermore, iPSC-derived bone marrow cells could differentiate into multiple lymphocyte lineages that reconstituted the lymphocyte population in syngeneic lethally irradiated recipient animals. Our results demonstrated that iPSCs have the inherent potential to differentiate into multiple lineages of functional lymphocytes without bias, and further support the practical application of iPSC-based treatments to hematological disorders.

Generation of Lungs by Blastocyst Complementation in Apneumic Fgf10-Deficient Mice

“…Genotyping revealed that 5 of 20 chimeras (40%) were derived from Fgf10 Ex1 mut /Ex3 mut embryos (Tables 1 and S2). The Fgf10 Ex1 mut /Ex3 mut chimeras exhibited a significant body-weight gain compared with Fgf10 wild-type and Fgf10 Ex1 mut /Ex3 mut mice, whereas no significant difference was observed between the groups of chimeric neonates (Figure S2B), which is consistent with previous observations (Lan et al, 2016;Mori et al, 2019). Macroscopic analysis and micro-CT confirmed the existence of a lung in the thoracic cavity of the Fgf10 Ex1 mut /Ex3 mut chimeras (Figures 2A and 2D; continuous CT images in Video 3).…”

Manufacturing Natural Killer Cells as Medicinal Products

“…Manufacturing of clinical-grade NK cells from either embryonic (ES) or induced pluripotent stem (iPS) cells nowadays appear as a futuristic option, although preclinical demonstrations that NK cells can be differentiated from these sources of pluripotent stem cells were already published (54–56). For iPS cells, several factors affect the pluripotency and differentiation abilities of reprogramed cells: the choice of target donor somatic cell type and the reprograming protocol, including the nature and combination of genes as well as the method used to deliver transcription factors into somatic cells (57).…”

iPS Cells—The Triumphs and Tribulations

“…Thus, an altered approach is desired which can offer identical environment as human cells and iPSCs seem like an amenable substitute with plethora of advantages. iPSCs do not require multiple proliferation and their derivatives are functional after transplantation in vitro as well as in vivo [ 39 , 40 , 41 , 42 , 43 ]. Hence iPSCs are used in therapeutics for disease modelling, drug screening and regenerative medicine.…”