BACH1 governs macrophage plasticity and niche adaptation during skeletal muscle regeneration

Abstract

Successful tissue regeneration requires a precisely coordinated transition from inflammation to resolution and repair. Macrophages are central to this process because they dynamically adapt their transcriptional and functional states to the changing tissue environment. This thesis investigates the role of the heme-responsive transcription factor BACH1 in macrophage plasticity and skeletal muscle regeneration. Using myeloid-specific Bach1 conditional knockout mice, bone marrow chimeras, bone marrow-derived macrophages, flow cytometry, single-cell and bulk RNA sequencing, chromatin accessibility profiling, myoblast differentiation assays, and histological analysis of cardiotoxin-injured muscle, this work defines the cell-intrinsic and tissue-level functions of BACH1. Loss of BACH1 induced a primed macrophage state and exaggerated inflammatory responses. During muscle regeneration, BACH1 regulated chromatin accessibility and transcription-factor networks required for the appropriate progression of monocytes into resolving and repair-associated macrophages. In its absence, macrophage differentiation was accelerated but incomplete, resulting in cells that retained enhanced inflammatory programs, including elevated IL-1β, TNF, and IL-6 expression, while failing to acquire a fully functional reparative identity. Conditioned media from Bach1-deficient macrophages impaired myoblast differentiation, an effect partially reversed by IL-1β neutralization. Consistently, myeloid-specific Bach1 deletion caused persistent tissue damage, defective myofiber regeneration, and impaired structural recovery in vivo. Together, these findings establish BACH1 as a key epigenomic and transcriptional regulator that coordinates macrophage state transitions, niche adaptation, and the balance between inflammatory and regenerative programs during skeletal muscle repair.