Stimulating Fracture Healing in Ischemic Environments: Does Oxygen Direct Stem Cell Fate during Fracture Healing?

Abstract

Bone fractures represent an enormous societal and economic burden as one of the most prevalent causes of disability worldwide. Each year, nearly 15 million people are affected by fractures in the United States alone. Data indicate that the blood supply is critical for fracture healing; as data indicate that concomitant bone and vascular injury are major risk factors for non-union. However, the various role(s) that the vasculature plays remains speculative. Fracture stabilization dictates stem cell fate choices during repair. In stabilized fractures stem cells differentiate directly into osteoblasts and heal the injury by intramembranous ossification. In contrast, in non-stable fractures stem cells differentiate into chondrocytes and the bone heals through endochondral ossification, where a cartilage template transforms into bone as the chondrocytes transform into osteoblasts. One suggested role of the vasculature has been to participate in the stem cell fate decisions due to delivery of oxygen. In stable fractures, the blood vessels are thought to remain intact and promote osteogenesis, while in non-stable fractures, continual disruption of the vasculature creates hypoxia that favors formation of cartilage, which is avascular. However, recent data suggests that non-stable fractures are more vascularized than stable fractures, that oxygen does not appear associated with differentiation of stem cells into chondrocytes and osteoblasts, that cartilage is not hypoxic, and that oxygen, not sustained hypoxia, is required for angiogenesis. These unexpected results, which contrast other published studies, are indicative of the need to better understand the complex, spatio-temporal regulation of vascularization and oxygenation in fracture healing. This work has also revealed that oxygen, along with the promotion of angiogenesis, may be novel adjuvants that can stimulate healing in select patient populations.

Simulation Enabled Search for Explanatory Mechanisms of the Fracture Healing Process

“…2) Have sustained directional influences, spanning many TUs, guiding or constraining the direction and type of TU transitions. The latter may map to the combined net effects of multiple factors such as relative abundance and activity of immune cells [43] signaling influencing osteogenic and chondrogenic transcription networks [44], O2 gradients [45,46], and mechanical influences [47]. Callus Analog has achieved its current objectives without needing to bring any of those influences into focus, consistent with our strong parsimony guideline.…”

“…But because there are no material systems that can serve as analogical models, we are focusing on developing model mechanisms in software. [45]. The green shaded curve illustrates that, as one moves leftward, the number and variety of equally possible explanations increases dramatically, which can be a serious barrier to progress.…”

In vitro simulation of the early proinflammatory phase in fracture healing reveals strong immunomodulatory effects of CD146‐positive mesenchymal stromal cells

“…We here focused on secretory factors present in the early stage of bone healing and their influence on MSCs. However, cell–cell interactions as well as several other microenvironmental cues can modulate the phenotype of MSCs, for example, oxygen tension (Miclau et al, ) or biochemical and biophysical properties of the extracellular matrix (Rakian et al, ). Future studies will aim to develop appropriate 3D cell culture models mimicking the stem cell niche.…”

CoCl2, a mimic of hypoxia, enhances bone marrow mesenchymal stem cells migration and osteogenic differentiation via STAT3 signaling pathway

“…Hypoxia is a common pathological phenomenon during bone fracture healing due to disrupted blood supply (Aro et al, 1984;Kolar et al, 2011;Miclau et al, 2017). Hypoxiainducible factor 1-alpha (HIF-1a) is regarded as a main hypoxia-induced transcriptional regulator (Wang et al, 1995;Johnson et al, 2017).…”