Defective hematopoietic differentiation of immune aplastic anemia patient-derived iPSCs.

In acquired immune aplastic anemia (AA), pathogenic cytotoxic Th1 cells are activated and expanded, driving an immune response against the hematopoietic stem and progenitor cells (HSPCs) that provokes cell depletion and causes bone marrow failure. However, additional HSPC defects may contribute to hematopoietic failure, reflecting on disease outcomes and response to immunosuppression. Here we derived induced pluripotent stem cells (iPSCs) from peripheral blood (PB) erythroblasts obtained from patients diagnosed with immune AA using non-integrating plasmids to model the disease. Erythroblasts were harvested after hematologic response to immunosuppression was achieved. Patients were screened for germline pathogenic variants in bone marrow failure-related genes and no variant was identified. Reprogramming was equally successful for erythroblasts collected from the three immune AA patients and the three healthy subjects. However, the hematopoietic differentiation potential of AA-iPSCs was significantly reduced both quantitatively and qualitatively as compared to healthy-iPSCs, reliably recapitulating disease: differentiation appeared to be more severely affected in cells from the two patients with partial response as compared to the one patient with complete response. Telomere elongation and the telomerase machinery were preserved during reprogramming and differentiation in all AA-iPSCs. Our results indicate that iPSCs are a reliable platform to model immune AA and recapitulate clinical phenotypes. We propose that the immune attack may cause specific epigenetic changes in the HSPCs that limit adequate proliferation and differentiation.

Can pluripotent stem cells be used in cell-based therapy?

Pluripotent stem cells, both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have the ability to differentiate into several cell types that can be used in drug testing and also in the study and treatment of diseases. These cells can be differentiated by in vitro systems, which may serve as models for human diseases and for cell transplantation. In this review, we address the pluripotent cell types, how to obtain and characterize these cells, and differentiation assays. We also focus on the potential of these cells in clinical trials, and we describe the clinical trials that are underway.