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.
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.
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.