title: Ectopic bone formation in severely combat-injured orthopedic patients -- a hematopoietic niche.
abstract: Combat-related heterotopic ossification (HO) has emerged as a common and problematic complication of modern wartime extremity injuries, contributing to substantial patient morbidity and loss of function. We have previously reported that HO-forming patients exhibit a more pronounced systemic and local inflammatory response very early in the wound healing process. Moreover, traumatized muscle-derived mesenchymal progenitor cells from these patients have a skewed differentiation potential toward bone. Here, we demonstrate that HO lesions excised from this patient population contain highly vascularized, mature, cancellous bone containing adipogenic marrow. Histologic analysis showed immature hematopoietic cells located within distinct foci in perivascular regions. The adipogenic marrow often contained low numbers of functional erythroid (BFU-E), myeloid (CFU-GM, CFU-M) and multilineage (CFU-GEMM) colony-forming hematopoietic progenitor cells (HPCs). Conversely, tissue from control muscle and non-HO traumatic wound granulation tissue showed no evidence of hematopoietic progenitor cell activity. In summary, our findings suggest that ectopic bone can provide an appropriate hematopoietic microenvironment for supporting the proliferation and differentiation of HPCs. This reactive and vibrant cell population may help maintain normal hematopoietic function, particularly in those with major extremity amputations who have sustained both massive blood loss, prompting systemic marrow stimulation, as well as loss of available native active marrow space. These findings begin to characterize the functional biology of ectopic bone and elucidate the interactions between HPC and non-hematopoietic cell types within the ectopic intramedullary hematopoietic microenvironmental niche identified.
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD, USA. thomas.davis1@med.navy.mil
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Davis
authors.forename: Yelena
authors.initials: Y
authors.lastname: Lazdun
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Potter
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Forsberg
mesh_terms: D000293:Adolescent; D000328:Adult; D003114:Colony-Forming Units Assay; D003710:Demography; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D021621:Imaging, Three-Dimensional; D009985:Orthopedics; D009999:Ossification, Heterotopic / Q000000981:diagnostic imaging / Q000473:pathology*; D010012:Osteogenesis; D055153:Stem Cell Niche; D014057:Tomography, X-Ray Computed; D014947:Wounds and Injuries / Q000000981:diagnostic imaging / Q000473:pathology*; D055815:Young Adult
keywords: ACL; BFU-E; CFC; CFU; CFU-GEMM; CFU-GM; CFU-M; EIH; EMH; Ectopic bone; Extremity injuries; HO; HPC; Hematopoiesis; Hematopoietic niche; Heterotopic ossification; ISS; MMP; MSC; PHSC; anterior cruciate ligament; burst forming unit-erythroid; colony forming unit; colony forming unit-granulocyte and macrophage; colony forming unit-macrophage; colony-forming cell; ectopic intramedullary hematopoiesis; extramedullary hematopoiesis; hematopoietic progenitor cell; heterotopic ossification; injury severity score; matrix metalloproteinase; mesenchymal stem cell; multilineage colony forming unit-granulocyte, macrophage and megakaryocyte; pluripotent hematopoietic stem cells