The pathologically altered bone marrow (BM) niche in BM fibrosis is induced by injury in the form of a malignant hematopoietic clone causing high concentrations of inflammatory cytokines that activate macrophages (and megakaryocytes) into a profibrotic state. This induces the fibrotic transformation of stromal cells and ECM deposition over time. Following allogeneic hematopoietic stem cell transplantation (allo-HSCT), a sequential transition occurs: the elimination of the malignant clone (the injury stimulus) leads to a rapid decline in inflammatory signaling, which triggers the normalization of macrophages toward a homeostatic state and facilitates the enzymatic remodeling of the fibrotic matrix. This “regenerative reset” culminates in a restored niche where donor-derived hematopoietic and immune cells maintain balanced signaling, allowing stromal cells to revert to a quiescent phenotype or be replaced by healthy niche cells. This natural experiment demonstrates that removing the initiating driver and reprogramming the immune microenvironment can drive the transition from advanced fibrosis back toward tissue homeostasis.