Transplanted ER-MP12hi20−58med/hi myeloid progenitors produce resident macrophages from marrow that are therapeutic for lysosomal storage disease

Lysosomal storage diseases (LSD) respond to bone marrow (BM) transplantation when donor-derived cells deliver needed enzyme. Hypothetically, the ubiquitous resident macrophages (MΦ) are the primary delivery vehicle of therapeutic protein. In mucopolysaccharidosis type VII (MPS VII) mice with LSD, transplanted mature MΦ reduce undegraded glycosaminoglycans (GAG) in the lysosome but are incapable of self-renewal, leading to return of storage after 1 month. We show here that a population of early BM-derived myeloid progenitors devoid of long-term hematopoietic stem cells (LT-HSC) engrafted MPS VII BM, released monocytes into peripheral blood (PBL), and engrafted tissues at known sites of resident MΦ. These primitive Mac-1− cells were sorted from normal whole BM and were defined by ER-MP12hi20−58med/hi labeling. Lysosomal storage was reduced in liver, spleen, thymus, heart, kidney, and bone. Cells persisted for 3 months, suggesting self-renewal capacity or a long half-life. Cells sorted from BM by ER-MP12−20hi marker expression (which are maturer myeloid cells that express Mac-1) engrafted tissues instead of BM and quantitatively repopulated less than cells derived from the ER-MP12hi20−58med/hi population. Also, reduction of lysosomal storage was variable and generally less when compared to that following transplantation of immature ER-MP12hi20−58med/hi cells. We conclude that primitive myeloid progenitors are more therapeutic for LSD than mature myeloid cells due to their greater longevity and increased capacity to seed tissues. The ability of cells derived from these primitive precursors to seed deep within tissues make them excellent candidates for both cellular therapy and gene transfer techniques to cure a wide range of metabolic diseases.