Generating functional haematopoietic stem cells (HSCs) from human pluripotent stem cells remains a major goal for both regenerative medicine and the study of early human blood development. Achieving this requires a clear understanding of how HSC identity is established during embryogenesis and how these developmental cues can be recreated in vitro. Recent work from Prof. Hanna Mikkola's group has defined transcriptional signatures and niche interactions that mark the emergence and maturation of human HSCs in vivo. Complementary studies from Professor Elizabeth Ng's team have developed human pluripotent stem cell-based systems that recapitulate key stages of this ontogeny, generating haemogenic endothelium and HSC‑like cells capable of long‑term multilineage engraftment. In this perspective, drawing on the recent ISEH NIC webinar presented by Profs. Mikkola and Ng, we integrate insights from both developmental and engineered systems to outline shared principles of human HSC formation and highlight opportunities to refine in vitro strategies for producing fully functional HSCs. Teaser Abstract What can human development teach us about building haematopoietic stem cells in the laboratory? Inspired by presentations from Profs. Mikkola and Ng at the 2025 ISEH NIC webinar, this perspective highlights the developmental and engineering principles that underpin human HSC formation and considers how these insights are advancing efforts to generate durable, engraftable HSCs for translational and regenerative applications.
Chromatin remodeling by mammalian SWI/SNF complexes is essential for hematopoietic lineage specification and differentiation. Although the canonical BAF subunits ARID1A and ARID1B are recurrently altered in B-cell malignancies, their overlapping and stage-specific functions during B-cell development remain incompletely understood. Here, we used CD19-Cre-mediated deletion of Arid1a and Arid1b to define their roles in B-cell development and hematopoietic transformation in vivo. Loss of either Arid1a or Arid1b impaired B-cell differentiation, reduced immature and recirculating B-cell output, and compromised germinal center responses following antigen challenge, with more pronounced defects following combined deletion. Unexpectedly, combined Arid1a/Arid1b loss resulted in a lethal, transplantable myeloid leukemia rather than a B-cell malignancy. CD19-Cre lineage tracing and allele-recombination analysis identified a subset of multipotent progenitors carrying CD19-Cre activity, while combined deletion was associated with selective MPP3 expansion and impaired myelo-erythroid colony-forming capacity. Transcriptional profiling of Arid1a/Arid1b-deficient MPP2/3 cells revealed loss of HSPC- and lymphoid-associated programs together with aberrant activation of erythroid and megakaryocyte-erythroid transcriptional states, without acquisition of a conventional mature myeloid program. These findings reveal overlapping functions of ARID1A and ARID1B in B-cell development and support a broader role for canonical BAF complexes in maintaining hematopoietic lineage fidelity and constraining malignant transformation.
