Trauma and Stem Cells: Biology and Potential Therapeutic Implications

Abstract

Trauma may cause irreversible tissue damage and loss of function despite current best practice. Healing is dependent both on the nature of the injury and the intrinsic biological capacity of those tissues for healing. Preclinical research has highlighted stem cell therapy as a potential avenue for improving outcomes for injuries with poor healing capacity. Additionally, trauma activates the immune system and alters stem cell behaviour. This paper reviews the current literature on stem cells and its relevance to trauma care. Emphasis is placed on understanding how stem cells respond to trauma and pertinent mechanisms that can be utilised to promote tissue healing. Research involving notable difficulties in trauma care such as fracture non-union, cartilage damage and trauma induced inflammation is discussed further.

Keywords: DAMP; healing; inflammation; stem cells; trauma.

Figure 1

Totipotent cells of the blastocyst are capable of differentiation into embryonic and placental tissue. Stem cells can be grouped into three primary dermal layers (endodermal, ectodermal and mesodermal) and eventually mature into various somatic cells. Induced pluripotent stem cells (iPSC) are formed when somatic cells are manipulated to regress their maturity.

Figure 2

Various stem cell mechanisms are activated in response to severe injury. (1) Fracture healing involves multiple stem cells. Satellite cells play a vital role in activating Periosteal Stem Cells to release osteogenic and chondrogenic factors while also migrating to the fracture site to augment fracture healing directly. ADSC and ESC also migrate to the fracture site. (2) The SDF-1/CXCR4 axis facilitates migration of MSC away from bone marrow towards sites of injury. G-CSF (Granulocyte Colony Stimulating Factor) also favours release of stem cells from bone marrow. Severe injury is accompanied by bone marrow failure and expulsion of bone marrow stromal cells. Some of the circulating stem cells sequester in lung and liver parenchyma. (3) Coagulation occurs with the healing response to injury while severe trauma may result in coagulopathy. There is an increase in platelet factors and thrombin as a result, which is chemotactic to MSC. (4) Inflammation and immune activation follows injury and inadvertently involves stem cell function. DAMPs and complement proteins may activate and prime MSC while also stimulating Polymorphonuclear Granulocyte (PMN) to damage neighbouring MSCs. MSCs may be polarized into pro-inflammatory or anti-inflammatory phenotypes depending on the nature of Toll-like Receptor(TLR) activation. TLR-4 activation results in pro-inflammatory MSCs while TLR-3 activation gives rise to anti-inflammatory MSCs. MSCs also possess the ability to donate mitochondria to neighbouring damaged cells to improve cell survival.