These results demonstrate an imbalance of bone formation and resorption parameters in patients with traumatic brain injury during the early posttraumatic period, suggesting a central regulation in bone formation. The lower levels of osteocalcin detected in this study may play an important role in patients with brain injury and the later development of posttraumatic heterotopic ossification.
The present Study investigated the intrinsic ability of adipose tissue-derived stem cells (ADSCs) and their neural transdifferentiation in a stage-specific manner. Woodbury’s Chemical induction was implemented with modifications to achieve neural transdifferentiation. In Group I, ADSCs were preinduced with β-mercaptoethanol (β-ME) and later, with neural induction medium (NIM). In Group II, ADSCs were directly treated with NIM. In Group III, a DNA methyltransferase (DNMT) inhibitor 5-azacytidine was applied to understand whether transdifferentiation is controlled by epigenetic marks. Irrespective of the presence of (β-ME), the differentiation protocol resulted in glial-lineage cells. Group III produced poorly -differentiated neural cells with neuron-specific enolase positivity. A neuroprogenitor stage (NPC) was identified at d 11 after induction only in Group I. In other groups, this stage was not morphologically distinct. We explored the stage-specific incidence NPC, by alternatively treating them with basic fibroblast growth factor (bFGF), and antioxidants to validate if different signalling could cause varied outcomes (Group IV). They differentiated into neurons, as defined by cell polarity and expression of specific proteins. Meanwhile, neuroprogenitors exposed to NIM (Group I) produced glial-lineage cells. Further refinement and study of the occurrence and terminal differentiation of neuroprogenitors would identify a promising source for neural tissue replacement.
Heterotopic ossification (HO) is the pathologic formation of bone in soft tissue. The exact pathomechanism is unknown but probably involves a disturbed osteoblast differentiation. Leptin, known as the obesity gene, may regulate normal osteoblast function in vitro. The aim of the present in vitro study was to further analyze the pathomechanisms of HO, including a possible role of leptin in ectopic bone formation. Human osteoblasts were cultivated either from normal bone or from resected HO. Both groups were incubated with increasing doses of leptin. Phenotype expression and mineralization of extracellular matrix were measured after 7, 14, and 21 days. In both groups, leptin increased both the formation of bone nodules and Ca-45 incorporation. This is the first study to analyze the effect of leptin on bone cells from ectopic ossification. Similar to the in vitro behavior of normal osteoblasts, cells from HO respond to leptin exposure with an increased mineralization of the extracellular matrix. This mechanism may be involved in the pathogenesis of ectopic bone formation in vivo.
Systemic factors are believed to be pivotal for the development of heterotopic ossification in severely-injured patients. In this study, cell cultures of putative target cells (human fibroblastic cells, osteoblastic cells (MG-63), and bone-marrow stromal cells (hBM)) were incubated with serum from ten consecutive polytraumatised patients taken from post-traumatic day 1 to day 21 and with serum from 12 healthy control subjects. The serum from the polytraumatised patients significantly stimulated the proliferation of fibroblasts, MG-63 and of hBM cells. The activity of alkaline phosphatase in MG-63 and hBM cells was significantly decreased when exposed to the serum of the severely-injured patient. After three weeks in 3D cell cultures, matrix production and osteogenic gene expression of hBM cells were equal in the patient and control groups. However, the serum from the polytraumatised patients significantly decreased apoptosis of hBM cells compared with the control serum (4.3% vs 19.1%, p = 0.031). Increased proliferation of osteoblastic cells and reduced apoptosis of osteoprogenitors may be responsible for increased osteogenesis in severely-injured patients.
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