Around 20,000 hematopoietic transplantations are performed annually to treat a variety of hematopoietic diseases, often as a last resort. Given the importance of hematopoietic transplantation in the clinic, many studies have been conducted to fully understand engraftment and the generation of the immune system post-transplantation.

Currently, the developmental dogma of hematopoiesis states that all lymphoid and myeloid cells develop from long-term hematopoietic stem cells (LT-HSCs), a theory based on the “layered immune system” hypothesis proposed by Herzenburg and Herzenburg in 1989. This hypothesis states that hematopoietic development is not linear, but rather follows three waves during embryonic and postnatal development. The first two hypothesized waves of primitive cells and erythromyeloid progenitors (EMPs) are thought to be embryonically transient, and do not contribute to postnatal hematopoiesis. As initially demonstrated in mice, the third wave, HSCs, was thought to drive the development of the entire murine blood lineage starting at embryonic day 11 (E11) and onwards through adult life. However, recent studies have challenged this dogma, suggesting that alternative, HSC-independent developmental routes for immune cells exist.

One hypothesis argues that specific fetal cells have the capability to generate innate immune lineage cells and lymphoid progenitors prior to HSC emergence, which has the potential to alter the long-standing theory that all cells of the blood lineage are HSC-dependent. The identification of specific subsets of B cells, including marginal zone B, B2, B1-b and B1-a cells, lead to researchers inquiring as to the differences in developmental programs from which each subset arises. Surprisingly, researchers were able to show that purified murine fetal liver derived LT-HSCs cannot reconstitute the B1-a compartment upon transplantation to immunocompromised mice. Furthermore, this group was able to reconstitute B1-a cells when transplanting fetal liver cells lacking LT-HSCs, suggesting that there must be an alternative progenitor to B1-a cells found in the fetal liver. In further support of this alternative hypothesis, researchers have found progenitors with multipotent myeloid and lymphoid potential in the mouse at E9, earlier than HSC emergence at E11. Taken together, these findings support the existence of HSC-independent innate immune cells of fetal origin.

HSC diagram
The “layered immune system” hypothesis proposed in 1989 identifies three waves of hematopoietic development, starting with primitive cells, then erythromyeloid progenitors (EMPs), and finally hematopoietic stem cells (HSCs) which are thought to give rise to the entire mouse blood lineage. Since then, multipotent myeloid and lymphoid progenitors have been discovered that are physically and temporally distinct from HSCs, but emerge from a common hemogenic endothelium origin. Image credit: Angela Zhou.

One major question raised by the above findings is if these cells are not HSC-derived, what could be their source? Follow-up studies demonstrated that HSC-independent early myeloid progenitors, B1-a cells, and HSCs themselves come from blood vessel cells called hemogenic endothelial cells. Fate-mapping studies illustrate that these alternative cell populations are not derived from HSCs; despite a common hemogenic endothelial origin, the non-traditional progenitors arise from cell populations that are physically and temporally distinct from HSCs. Thus, the capacity for hemogenic endothelial cell subsets to give rise to these EMPs and B1-a cells supports an HSC-independent model of development for certain myeloid and lymphoid lineages.

Given the development of immune lineages independent of the HSC, one major concern raised by these studies is whether or not the current method of transplantation can fully reconstitute the human immune system, as it relies solely on HSC engraftment. The implications from these studies in mice suggest that a patient’s immune system might not be fully functional after HSC transplantation, as it may be missing key populations derived from the non-traditional progenitors of hemogenic origin. Indeed, B1-a cells have been shown to be critical for protective immune responses against bacterial, viral and fungal pathogens; given that about 20% of patients who receive stem cell transplants die of infection post-transplant, it would be of great clinical significance to determine the exact extent of reconstitution following transplant and whether there is a critical absence of HSC-independent populations. Further research into these paradigm-shifting discoveries will lead to a more comprehensive view of hematopoietic development and potentially translate positively to the clinic.


  1. Chen MJ, Li Y, De Obaldia ME, et al. Erythroid/myeloid progenitors and hematopoietic stem cells originate from distinct populations of endothelial cells. Cell stem cell 2011; 9(6): 541-52.
  2. Ghosn Eliver Eid B, Waters J, Phillips M, et al. Fetal Hematopoietic Stem Cell Transplantation Fails to Fully Regenerate the B-Lymphocyte Compartment. Stem Cell Reports 2016; 6(1): 137-49.
  3. Herzenberg LA, Herzenberg LA. Toward a layered immune system. Cell 1989; 59(6): 953-4.
  4. Pasquini MC, and Zhu, X. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR summary slides. Available at: 2014.
  5. Yoshimoto M, Montecino-Rodriguez E, Ferkowicz MJ, et al. Embryonic day 9 yolk sac and intra-embryonic hemogenic endothelium independently generate a B-1 and marginal zone progenitor lacking B-2 potential. Proceedings of the National Academy of Sciences of the United States of America 2011; 108(4): 1468-73.
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Mark Gower

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