hsc-independent hematopoiesis


The current paradigm posits that a single hematopoietic stem cell (HSC) regenerates all components of the immune system. As a result, today more than 20,000 HSC transplantations are performed every year to restore immunity in immune-compromised patients (e.g., to treat lymphomas, leukemias, myelomas, and immunodeficiency disorders) (Pasquini and Zhu, 2014).


However, our recent studies in murine HSC transplantation (Ghosn et al., PNAS 2012; Ghosn et al., Ann. N. Y. Acad. Sci. 2015; and Ghosn et al., 2016 Stem Cell Reports) have challenged this broadly accepted paradigm and establish a novel concept of HSC-independent hematopoiesis (Figure 3). In essence, we showed that long-term (LT)-HSCs, purified from fetal liver and adult bone marrow, selectively fail to regenerate B-1a, a subset of tissue-resident lymphocytes that secrete most of the natural antibodies in serum and is required for protection against Pneumonia, Influenza, and other infectious diseases.

Ghosn EE et al. Fetal HSC transplantation fails to fully regenerate the B-lymphocyte compartment. Stem Cell Reports 2016

Similarly, data from our LT-HSC transplantations combined with in vivo lineage tracing studies show that certain tissue-resident macrophages, such as brain microglia, originate independently of LT-HSCs. Taken together, these findings now overtly challenge the broadly accepted paradigm that HSC transplantation fully regenerates all components of the immune system.

Ghosn EE & Yang Y. Hematopoietic stem cell-independent B-1a lineage. Ann NY Acad Sci. 2015

Because about 20% of patients die post-HSC transplantation due to infectious diseases, our data showing that murine HSC transplantation fails to reconstitute a key component of the humoral immune system open the broad question of whether humans, like mice, generate tissue-resident B lymphocytes and macrophages (and other hematopoietic lineages) independently of HSCs and, if so, whether these immune cells play critical roles that may help protect HSC-transplanted patients from subsequent infections and other post-transplant diseases. Our current research projects are tackling these and other related questions.

Determining the developmental pathway(s) of HSC-independent and HSC-dependent immune cells will provide a richer view of the functionality of the immune system and the ways by which evolution has addressed different needs encountered at different developmental stages, from fetal life through adulthood. At a minimum, these findings change our current understanding of the developmental landscape of the immune system by challenging the notion that LT-HSCs fully reconstitute all components of the immune system. 


current projects