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Hematopoietic stem cells (HSCs) give rise to all blood and immune cells in the body. These rare cells reside in the hypoxic niche of the bone marrow (BM) where they are subjected to a complex network of regulatory factors including cellular and molecular components. To sustain hematopoiesis over the lifetime of an individual, HSCs maintain distinctive metabolic programs, and in recent years nutritional factors have been increasingly recognized as critical regulators of HSC numbers and functions. Leptin (LEP), a neuroendocrine messenger, and its receptor (LEPR) are well-known for their immunomodulatory and energy balancing effects; yet, how LEP/LEPR signaling plays a role in hematopoiesis is under-appreciated. In this review, we summarize and highlight recent work that demonstrated involvement of LEP/LEPR in hematopoiesis under steady state or stress-associated situations as well as in pathological conditions such as cardiovascular diseases and malignancies. Although the field is only in its infancy, these studies suggest evidence of potential clinical applications and proof-of-principle for more in-depth future research. Under steady state, only a minor subset of long-term hematopoietic stem cells (HSCs) express LEPR. Upon irradiation, LEPR + HSCs exhibited robust repopulating capacity in long-term engraftment studies that outcompeted LEPR - HSCs. LEPR + stromal cells secrete critical niche factors including stem cell factor (SCF) and pleiotrophin (PTN) to support HSCs and progenitor cells. LEPR signaling mediated protective effects of fasting in ALL but not AML leukemias.

Role for Leptin and Leptin Receptors in Stem Cells During Health and Diseases