Interactions of Stem Cells and Immune Cells in Bone Healing

This open access review paper looks over what is known of the role of the immune system in bone regeneration. A variety of immune cells play important roles in tissue regeneration, but these activities are not yet fully cataloged and understood, and are different in different tissues. Since the immune system declines with age, along with the stem cell populations that provide signals and a supply of new cells for tissue maintenance, it is likely that this is one of the causes of failing regeneration in older individuals.

Bone fractures are among the most common orthopedic problems that require medical intervention, particularly in the elderly. Almost half of fractures are related to osteoporosis, especially in individuals over the age of 55. Bone injury leads to the production of pro-inflammatory cytokines and chemokines and to systemic recruitment of macrophage precursors to the injury site. Bone healing is a complex process and there appears to be a deficiency in our understanding of the interactions between macrophages and mesenchymal stem cells (MSCs) in bone healing, especially in the elderly population. Specifically, aging may alter these interactions and thereby play an important role in the elderly patient's ability for regeneration of musculoskeletal tissues.

As such, it is important to understand the different macrophage populations that play a role in bone repair. Though they exist within a spectrum, macrophages can be broadly described as uncommitted M0, pro-inflammatory M1, and anti-inflammatory M2 populations. In actuality, both in humans and mice, there probably exists a spectrum of polarization phenotypes, with a general preponderance of pro- versus anti-inflammatory properties. With these multiple phenotypes, macrophages play several roles within the bone-healing process, depending on their polarization status and environmental cues.

Although it is apparent that macrophages have altered activities with age, it is unclear as to what these specific changes entail and the mechanisms that drive such changes in musculoskeletal tissues. Several studies point to intrinsic factors that alter macrophage polarization, function, and survival. It was found that aged muscle had higher levels of M2a polarized macrophages, muscle fibrosis, and collagen accumulation. The increased frequency of M2a macrophages and fibrosis was attributable to the aging of myeloid lineage cells, as demonstrated by rescue of aged muscle with infusion of young bone marrow cells. In addition to intrinsic changes of aging, macrophages are modulated by their aging microenvironment and a poorly described number of external factors. When challenging young macrophages with aged serum, studies found reduced macrophage secretion of TNF╬▒ and increased basal levels of IL-6. In a study comparing phagocytosis by young and aged peritoneal macrophages and bone marrow-derived macrophages, it was demonstrated that older peritoneal macrophages have significantly impaired phagocytosis compared with younger macrophages.

Aging is also associated with elevated levels of secreted inflammatory cytokines beyond the previously described functional and environmental changes. Much of the literature describes aged macrophage hypersensitivity and increased responsiveness to inflammatory signals. These findings suggest that aged macrophages remain in a pre-activated resting state that enhances their response to exposure of pro-inflammatory stimuli. However, with increased production of reactive oxygen species, aged macrophages are susceptible to oxidative damage. Although there is increased responsiveness to pro-inflammatory signals, aged macrophages also have impaired function with reduced phagocytic activity, reduced nitrite burst capacity, and reduced autophagy.

Given current knowledge, it is apparent that aging-associated changes in the macrophage population are normal events but can also be potential sources for pathological states. With aging, the proliferative and functional abilities of macrophages and MSCs are impaired because of a combination of intrinsic and environmental factors. As proper bone healing requires an inflammatory phase, the increased survival of anti-inflammatory M2 macrophages and reduced secretion of pro-inflammatory factors with age may jeopardize timely bone regeneration. At the same time, aging negatively impacts MSC proliferation and differentiation, further impeding the bone-healing process. It would appear that, taken together, both macrophages and MSCs, cells critical for regeneration of musculoskeletal tissues, are adversely affected by aging. This scenario provides new opportunities for modulation of cellular events in order to optimize the healing of mesenchymally derived tissues, including bone.



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