Aging as a Potential Modulator of Extramedullary Hematopoiesis: A Hypothesis-Generating Niche-HSPC Competence-Trigger...

Extramedullary hematopoiesis (EMH) is a compensatory response to hematopoietic stress that occurs unevenly across disorders with ineffective erythropoiesis (IE). The mechanisms underlying differing EMH patterns despite similarly severe IE remain poorly understood. Thalassemia and congenital dyserythropoietic anemias frequently develop overt EMH, whereas myelodysplastic syndromes (MDS), despite severe IE, rarely show overt EMH. We propose the Niche- HSPC Competence-Trigger Model as a hypothesis-generating framework in which EMH expression reflects the interaction among erythropoietic trigger load, intrinsic hematopoietic stem and progenitor cell (HSPC) competence, and extramedullary niche fitness. Erythropoietic trigger load reflects the intensity and persistence of erythropoietic stress, particularly anemia and hypoxia, in disorders characterized by ineffective erythropoiesis. HSPC competence refers to the intrinsic capacity of HSPCs for proliferation and differentiation, whereas extramedullary niche fitness denotes the capacity of target tissues to support HSPC homing, engraftment, survival, expansion, and productive hematopoiesis; this capacity is shaped by stromal and vascular integrity, inflammatory and fibrotic remodeling, metabolic support, and iron availability. Within this framework, overt EMH is hypothesized to be favored when erythropoietic drive coincides with preserved HSPC competence and extramedullary niche fitness. Conversely, impaired HSPC competence or reduced niche fitness may limit overt EMH, while whether subclinical extramedullary hematopoietic activity occurs in MDS remains unresolved. We hypothesize that aging may modulate this balance by influencing both HSPC competence and niche fitness, thereby potentially contributing to the rarity of overt EMH in MDS. These hypotheses, including the contribution of aging and the possible occurrence of subclinical extramedullary hematopoietic activity, require experimental and clinical validation.