Promise and challenges of human iPSC-based hematologic disease modeling and treatment

Abstract

Postnatal hematopoietic stem cells (HSCs) from umbilical cord blood and adult marrow/blood have been successfully used for treating various human diseases in the past several decades. However, the availability of optimal numbers of HSCs from autologous patients or allogeneic donors with adequate match remains a great barrier to improve and extend HSC and marrow transplantation to more needing patients. In addition, the inability to expand functional human HSCs to sufficient quantity in the laboratory has hindered our research and understanding of human HSCs and hematopoiesis. Recent development in reprogramming technology has provided patient-specific pluripotent stem cells (iPSCs) as a powerful enabling tool for modeling disease and developing therapeutics. Studies have demonstrated the potential of human iPSCs, which can be expanded exponentially and amenable for genome engineering, for using in modeling both inherited and acquired blood diseases. Proof-of-principle studies have also shown the feasibility of iPSCs in gene and cell therapy. Here, we review the recent development in iPSC-based blood disease modeling, and discuss the unsolved issues and challenges in this new and promising field.

Differential Sensitivity to JAK Inhibitory Drugs by Isogenic Human Erythroblasts and Hematopoietic Progenitors Generated from Patient-Specific Induced Pluripotent Stem Cells

“…Patient-iPSCs can be expanded without limits and redifferentiated back to the cell types most relevant to the disease and drug targets [3, 15]. In addition, the clonality of iPSCs that capture the exact genetic complement of a parental somatic cell makes it possible to determine the drug effects specific to the investigated genotype.…”

“…Disease-specific induced pluripotent stem cells (iPSCs) provide an unprecedented opportunity to establish novel human cell-based disease models and accelerate drug development [1][2][3]. In addition to the recent success of modeling inherited forms of blood disorders [4][5][6][7][8][9], progress in integration-free reprogramming of human blood cells through episomal vectors [10][11][12] has made it more feasible to develop iPSC models for studying acquired blood diseases such as myeloproliferative neoplasms (MPNs), aplastic anemia, myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria, and many forms of leukemia.…”

Efficient and Scalable Expansion of Human Pluripotent Stem Cells Under Clinically Compliant Settings: A View in 2013

“…68,86, 110 Another potential clinical application of hiPSCs, gene-correction based stem cell therapy, 61 would use the strategy of deriving an iPSC line from a patient with a disease caused by a genetic defect such as sickle cell disease. 127 Such diseases could then be treated by gene correction using zinc finger nuclease (ZFN), 134 transcription activator-like effector nuclease (TALENs), 39 or the newly reported CRISPR/Cas9 system 62 to repair the endogenic pathogenic mutations, after which they repaired genes would be expanded and differentiated into desired cell types for pathology study or transplantation purpose. For additional reading, please refer to thorough reviews about the use of hiPSCs in disease modeling and gene therapies by Robinton et al and Merkle et al 69, 89 To keep its focus on the expansion of hPSCs, this review will consider several prominent aspects for developing bioprocess of hPSC expansion.…”

Back to the future: how human induced pluripotent stem cells will transform regenerative medicine

“…In nearly all cases, differentiation seems to produce immature cells but not mature functional cells required for tissue repair. Perhaps the best example comes from efforts to produce functional blood cells from human iPSCs, where there has been little success in generating a cell type that will engraft into the bone marrow of irradiated mice—one of the features of mature blood cells (29). Another comes from many studies attempting to make functional islet cells from hESCs or hiPSCs as a source of tissue for treating diabetes.…”