​How does inflammation impact HSC fate to alter blood production?

How is HSC function impacted by chronic inflammatory disease?

Does chronic inflammation drive leukemia development and progression?

Inflammation evolved as an ‘emergency’ response that is turned on and off quickly to avoid causing damage to our tissues. Nonetheless, it is a double-edged sword. Chronic inflammation, in which this response fails to turn off, is a key pathological component of a bewildering array of severe metabolic and autoimmune diseases, including atherosclerosis, obesity, diabetes and arthritis. Each of these conditions has distinct origins and pathologies, but all of them are marked by severely deregulated blood regulation that leads to:

1. The overproduction of myeloid cells which propagates tissue damage
2. Loss of erythrocyte production leading to anemia of chronic disease
3. Greatly impaired immune system function that worsens the underlying disease and leaves patients vulnerable to infection.

We suspect the same inflammatory signals that activate HSCs in response to acute need alter their fate and function during chronic exposure, thereby creating a deregulated hematopoietic hierarchy that in essence underwrites the disease phenotype. We are therefore investigating the long-term consequences of chronic inflammation on HSC function using mouse models of these diseases, and whether blockade of inflammatory signals can normalize HSC function and reduce disease severity.

Many leukemias have been classically viewed to be the result of certain mutations that transform normal cells into leukemic stem cell (LSCs) clones, which in turn initiate and propagate disease. More recently, leukemia development is being viewed as a partnership between transforming mutations and deregulation of the microenvironment around the leukemic cells. Interestingly, many cancers, and in particular preleukemic clonal blood disorders such as myelodysplastic syndrome are associated with prior underlying chronic inflammatory disease.

We suspect that chronic exposure to pro-inflammatory factors not only deregulates blood production by HSCs, but may also make them vulnerable to leukemic transformation. We also hypothesize that in the context of leukemia, inflammatory signals serve as growth and survival factors for LSCs. We are now investigating whether inflammation can drive cellular transformation and disease progression using several mouse genetics approaches, and whether these represent targets for novel anti-leukemia therapy.​

The blood system | A dynamic tissue​

The blood is a fascinating liquid tissue, consisting of millions of cells distributed among several distinct lineages including myeloid and lymphoid leukocytes (white blood cells) that allow us to fight infections, erythrocytes (red blood cells) that carry oxygen from our lungs to the rest of our tissues, and platelets that clot wounds to prevent blood loss. Like all tissues, the millions of cells that make up our blood system (traditionally referred to as the hematopoietic system) are derived from a complex cellular hierarchy fed by a small population of self-renewing hematopoietic stem cells (HSCs for short) that actively build the blood system during fetal development and subsequently become dormant as adulthood sets in, activating periodically to maintain the blood system for the rest of our lives. Inherent in the ability of our blood systems to respond to these diverse requirements is the capacity to rapidly adapt to specific needs, such as producing more myeloid cells following infection, or more erythrocytes to respond to the slightly thinner atmosphere while visiting, or living in, Denver.