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Unlocking the Power of iPSCs: A New Era in Hematopoietic Research

Human pluripotent stem cells (iPSCs) have revolutionized the landscape of biomedical research since their initial derivation in 1998 (Thomson et al., 1998) and the discovery that somatic cells could be reprogrammed to a pluripotent state (Takahashi & Yamanaka, 2006; Takahashi et al., 2007). Their unique ability to proliferate indefinitely and differentiate into all cell types in the human body makes them a powerful tool for understanding human development and disease.

As the demand for more consistent, scalable and customizable cell models grows, iPSCs are becoming increasingly relevant in both basic research and therapeutic development. TrailBio® Hematopoietic Progenitor Cells provide researchers with reproducible, ready to use CD34 positive populations that eliminate donor variability and supply constraints.

The Current Landscape: Primary Cells vs. iPSC-Derived Hematopoietic Progenitor Cells (HPCs)

Traditionally, primary cells have been the go-to resource for researchers studying hematopoiesis. These cells, harvested directly from donors, offer a snapshot of in vivo differentiated blood cells and have been invaluable in understanding hematopoietic development (Doulatov et al., 2012), disease (Lapidot et al., 1994), drug discovery (Boitano et al., 2010), and toxicology applications (Vessillier et al., 2015). Despite their value, primary cells come with important limitations:

  • Donor variability: Genetic and epigenetic differences between donors can introduce inconsistencies in experimental outcomes. 
  • Limited availability: Access to specific donor profiles or rare cell types can be challenging and expensive. Disease samples may also have altered cellular composition, affecting the desired cell populations. 
  • Finite lifespan: Primary cells have limited proliferative capacity in vitro, requiring repeated sourcing and restricting long-term studies. 

In contrast, iPSC-derived HPCs can overcome many of these limitations. They can be generated from a single donor profile and expanded indefinitely, providing a consistent and renewable source of hematopoietic cells. Further, patient-derived iPSCs can also be generated and expanded without limit, removing the need for constant sourcing of scarce patient samples. While iPSC technology is still maturing, advances in formulation and differentiation protocols are steadily creating bridges between the functionality of iPSC-derived cells and that of primary cells.

Applications: Comparative Advantages of Primary and iPSC-Derived Cells

Both primary and iPSC-derived HPCs have distinct strengths, and understanding their comparative advantages helps researchers select the right tool for their application.

  1. Consistent Supply of HPCs
    • Primary Cells: The human body naturally produces hematopoietic cells in abundance, making primary cells relatively accessible. However, donor variability can lead to inconsistent results and complicate reproducibility.
    • iPSC-Derived HPCs: These cells can be manufactured repeatedly from the same donor profile, ensuring a consistent supply across batches. This is particularly valuable for high-throughput screening, drug development and disease modeling. Custom iPSC-derived profiles can also be generated to represent specific genetic backgrounds or disease states, providing tailored research tools. 
  1. Self-Renewal and Experimental Window
    • Primary Cells: Hematopoietic stem cells (HSCs) from primary sources tend to differentiate rapidly in culture, quickly losing stem-like properties and engraftment potential (Johnson et al., 2024). This narrow experimental window limits the time available for studies or manipulations. 
    • iPSC-Derived HPCs: Although iPSC-derived HPCs also differentiate quickly in vitro, ongoing work is hopeful to help slow differentiation kinetics in the future. 
  1. Lineage Differentiation Potential
    • Primary Cells: Having undergone natural development in vivo, primary cells exhibit broad lineage differentiation capabilities. They are considered the gold standard for generating mature blood cell types. Cord blood–derived CD34⁺ hematopoietic stem and progenitor cells, in particular, have demonstrated strong engraftment in xenograft models and clinical applications, underscoring their importance in both research and transplantation (Kim et al., 1999). 
    • iPSC-Derived HPCs: While iPSCs can differentiate into all blood lineages, differentiation protocols often introduce biases toward particular outcomes, for example, skewing toward myeloid over lymphoid potential. Recent work has shown that careful adjustment of signaling cues can improve balanced lineage output and engraftment (Ng et al., 2024), though engraftment remains lower than that achieved with cord blood CD34⁺ cells. Continued efforts to generate and maintain iPSC-derived HSCs that retain functional attributes for extended periods in vitro are essential to realizing the full potential of this technology. 

Improving iPSC-Derived HPC Protocols through High-Dimensional Design-of-Experiments

HD-DoE® (High-Dimensional Design-of-Experiments) offers a systematic approach to refining iPSC differentiation and maintenance through multi-parametric analysis. By probing the complex interplay of culture conditions, signaling pathways, and genetic factors, HD-DoE enables the creation of iPSC-derived HPCs that more closely replicate the properties of primary cells. These advances offer:

  • Reduced donor variability: A single donor profile can yield reproducible, standardized cell populations. 
  • Enhanced functionality: Improved culture conditions help preserve HSC markers and lineage potential.
  • Scalability: iPSC-derived cells can be generated at scale, meeting the needs of both research and translational applications. For users running multi plate assays or repeated screens, this means HPCs can be delivered in large, uniform lots rather than relying on multiple donor collections or batch-to-batch re-qualification.

This approach not only improves reproducibility but also lays the groundwork for personalized medicine, where patient-specific iPSC lines could be used to model disease, test therapies and ultimately develop cell-based treatments.

Conclusion 

The shift from primary donor-derived cells to iPSC-derived hematopoietic progenitors represents more than a technical upgrade; it signals a fundamental transformation in how blood cell research and applications can be approached. Primary cells remain the benchmark for engraftment and lineage diversity, yet their limitations in availability, variability and lifespan increasingly restrict their utility. iPSCs, by contrast, offer an inexhaustible and customizable platform, one that is already proving valuable in disease modeling, drug discovery and the design of more consistent assays. While challenges remain, particularly in generating long-term repopulating HSCs and overcoming lineage bias, ongoing innovations such as HD-DoE are helping to close the gap. Together, these advances point toward a future where scalable, patient-specific and reproducible iPSC-derived HPCs could further complement or even surpass primary sources, reshaping both basic research and translational medicine.

 Learn more about TrailBio® Hematopoietic Progenitor Cells

References 

  • Thomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshall, V.S. and Jones, J.M. (1998) ‘Embryonic stem cell lines derived from human blastocysts’, Science, 282(5391), pp.1145–1147. 
  • Takahashi, K. and Yamanaka, S. (2006) ‘Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors’, Cell, 126(4), pp.663–676. 
  • Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K. and Yamanaka, S. (2007) ‘Induction of pluripotent stem cells from adult human fibroblasts by defined factors’, Cell, 131(5), pp.861–872. 
  • Doulatov, S., Notta, F., Laurenti, E. and Dick, J.E. (2012) ‘Hematopoiesis: a human perspective’, Cell Stem Cell, 10(2), pp.120–136. 
  • Lapidot, T., Sirard, C., Vormoor, J., Murdoch, B., Hoang, T., Caceres-Cortes, J., Minden, M., Paterson, B., Caligiuri, M.A. and Dick, J.E. (1994) ‘A cell initiating human acute myeloid leukaemia after transplantation into SCID mice’, Nature, 367(6464), pp.645–648. 
  • Boitano, A.E., Wang, J., Romeo, R., Bouchez, L.C., Parker, A.E., Sutton, S.E., Walker, J.R., Flaveny, C.A., Perdew, G.H., Denison, M.S., Schultz, P.G. and Cooke, M.P. (2010) ‘Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells’, Science, 329(5997), pp.1345–1348. 
  • Vessillier, S., Eastwood, D., Fox, B., Sathish, J., Sethu, S., Dougall, T., Thorpe, S.J., Thorpe, R. and Stebbings, R. (2015) ‘Cytokine release assays for the prediction of therapeutic mAb safety in first-in-man trials—Whole blood cytokine release assays are poorly predictive for TGN1412 cytokine storm’, Journal of Immunological Methods, 424, pp.43–52. 
  • Kim, D.K., Han, S.B., Lee, S., Hong, K., Kim, B.S. and Kim, B.K. (1999) ‘Comparison of hematopoietic activities of human bone marrow and cord blood cells’, Stem Cells, 17(5), pp.286–294. 
  • Johnson, C.S., Williams, M., Sham, K., Belluschi, S., Ma, W., Wang, X., Lau, W.W.Y., Kaufmann, K.B., Krivdova, G., Calderbank, E.F., Mende, N., McLeod, J., Mantica, G., Li, J., Grey-Wilson, C., Drakopoulos, M., Basheer, S., Sinha, S., Diamanti, E., Basford, C., Wilson, N.K., Howe, S.J., Dick, J.E., Göttgens, B., Green, A.R., Francis, N. and Laurenti, E. (2024) ‘Adaptation to ex vivo culture reduces human hematopoietic stem cell repopulation capacity’, Blood, 144(7), pp.729–742. 
  • Ng, E.S., Davis, R.P., Stanley, E.G., Elefanty, A.G. and Alexander, W.S. (2024) ‘Long-term engrafting multilineage hematopoietic cells from human iPSCs’, Nature Biotechnology, 42, pp.1340–1352.