Elsevier

Biomaterials

Volume 32, Issue 2, January 2011, Pages 395-409
Biomaterials

Review
Stem cell homing in musculoskeletal injury

https://doi.org/10.1016/j.biomaterials.2010.08.101Get rights and content

Abstract

The regenerative potential of injured adult tissue suggests the physiological existence of cells capable of participating in the reparative process. Recent studies indicate that stem-like cells residing in tissues contribute to tissue repair and are replenished by precursor bone marrow-derived cells. Mesenchymal stromal cells (MSC) are among the candidates for reparative cells. These cells can potentially be mobilized into the circulation in response to injury signals and exert their reparative effects at the site of injury. Current therapies for musculoskeletal injuries pose unavoidable risks which can impede full recovery. Trafficking of MSC to the injury site and their subsequent participation in the regenerative process is thought to be a natural healing response that can be imitated or augmented by enhancing the endogenous MSC pool with exogenously administered MSC. Therefore, a promising alternative to the existing strategies employed in the treatment of musculoskeletal injuries is to reinforce the inherent reparative capacity of the body by delivering MSC harvested from the patient’s own tissues to the site of injury. The aim of this review is to inform the reader of studies that have evaluated the intrinsic homing and regenerative abilities of MSC, with particular emphasis on the repair of musculoskeletal injuries. Research that supports the direct use of MSC (without in vitro differentiation into tissue-specific cells) will also be reported. Based on accruing evidence that the natural healing mechanism involves the recruitment of MSC and their subsequent reparative actions at the site of injury, as well as documented therapeutic response after the exogenous administration of MSC, the feasibility of the emerging strategy of instant stem-cell therapy will be proposed.

Introduction

The ability of injured adult tissue to regenerate implies the existence of cells capable of proliferating, differentiating and/or functionally contributing to the reparative process [1]. Recent evidence suggests that stem-like cells that reside in multiple tissues participate in the course of tissue repair and are replenished by precursor cells from the bone marrow [2]. Among the candidates for reparative cells from bone marrow are the non-haemopoietic progenitor cells that exhibit a multi-lineage differentiation capacity, being able to differentiate into the osteogenic, myogenic, chondrogenic and neurogenic lineages [3]. These cells are commonly referred to as multipotent mesenchymal stromal cells, mesenchymal stem cells or marrow stromal cells (MSC). Current knowledge about MSC is based almost entirely on their in vitro characteristics. The native identity, exact location and functions of MSC in vivo remain elusive [4]. Besides the bone marrow, MSC and MSC-like cells have been found to be harbored in various other sites including adipose tissue, periosteum, skeletal muscle, placenta, trabecular bone and others [5]. These tissue-specific stem cells differ in phenotype, morphology, proliferation potential and differentiation capacity, but possess many common features associated with those from the bone marrow, possibly implying that MSC-like populations share a similar ontogeny [5]. Emerging evidence suggests that the perivascular niche could be the anatomic location where MSC-like populations reside in tissues [6], [7] and that pericytes may be integral to the origin of MSC [4], [8]. Notably, the recent paper by Crisan and colleagues [8] suggests that an ancestor of MSC is natively associated with the blood vessel wall and belongs to a subset of perivascular cells. Whether the vascular setting is indeed the actual niche for pericytic MSC-like cells and is the main source of MSC in vivo remains to be established [9].

MSC appear to be reservoirs of reparative cells that lack tissue-specific characteristics and can potentially be mobilized and differentiate into cells of a connective tissue lineage under different signals, such as damage from trauma, fracture, inflammation, necrosis and tumors [10]. Recent studies [11], [12] suggest that injury/trauma might initiate the mobilization of MSC into peripheral blood. These circulating stem cells are believed to home to the damaged or pathological tissues in a mechanism similar to leukocyte recruitment to sites of inflammation that involves adhesion molecules such as selectins, chemokine receptors and integrins. The migration of MSC from the circulation into injured or unhealthy tissues and the resulting therapeutic response have been documented [13], [14], [15], [16]. Increasingly, studies tend to conclude that the beneficial effects of MSC can be due to two possible mechanisms of reparative action [17]: not only the in situ differentiation of MSC to become normal constituents of the host cytoarchitecture and supporting stroma after recruitment to the injury site [18], but also to act via a paracrine mechanism. The latter is an emerging concept whereby MSC are believed to possess the capacity to home to the site of injury, and subsequently secrete a broad spectrum of paracrine factors that are both immunoregulatory and function to structure the regenerative microenvironment [19]. Caplan has referred to the regenerative microenvironment created by the bioactive factors secreted by MSC as ‘trophic activity’ [19]. Effects of these bioactive factors secreted include inhibition of scarring and apoptosis, and stimulation of angiogenesis and mitosis of tissue-intrinsic stem or progenitor cells [19].

Surgical procedures to repair or replace injured musculoskeletal tissues are the current gold standard for lost or damaged bone, cartilage or skeletal muscle. In cases of extensive bone loss, the reconstruction of large bone segments remains a significant clinical problem. Current therapeutic treatments include the use of particulate cancellous or bulk cortico-cancellous bone auto- or allografts, bone transport methods (Ilizarov technique), or implants made from natural or artificial materials. However, none has proven to be fully satisfactory [20]. Autologous bone graft is limited in supply and is often associated with significant donor-site morbidity, while the use of allografts or xenografts poses the potential risk of infection and of an adverse immune response by the host tissue after implantation. In addition, while biomaterials have the advantage of unlimited availability and good osteoconductivity, their application is limited as they lack osteoinductivity. The Ilizarov and related techniques take advantage of the regenerative potential of bone, however, these operations are painful and problematic for the patient and require weeks to months or longer before completion [20]. Current therapies presently employed for articular cartilage defects include autologous chondrocyte implantation (ACI), osteochondral autografts and allografts, microfracturing, mosaicplasty and in severe cases, total joint replacement [3]. ACI still faces several major challenges, including multiple surgical procedures, donor-site morbidity, chondrocyte de-differentiation during in vitro culture and fibrocartilage formation after cell implantation instead of defect healing [21]. These issues indicate that many current therapies for musculoskeletal repair have unavoidable risks which can have an impact on the patient’s ability to fully recover after surgery [3].

Studies suggest that trafficking of native MSC to injured tissue and their subsequent participation in the regenerative process is a natural healing response, which can potentially be imitated or augmented by enhancing the endogenous MSC pool with exogenously administered MSC. Accordingly, based on this hypothesis, a promising alternative to the existing therapeutic strategies employed in the treatment of musculoskeletal injuries is to reinforce the inherent reparative capacity of the body by delivering MSC harvested from the patient’s own tissues to the site of injury. Studies have already documented beneficial effects after the systemic or localized delivery of MSC for the repair of damaged cartilage [22], [23], [24], [25], [26], [27], [28], [29], [30], bone [13], [31], [32], [33], [34] and muscle [35], [36], [37].

The primary purpose of this review article is to inform the reader of studies that have evaluated the proposed intrinsic homing and regenerative abilities of MSC, with particular emphasis on the repair of musculoskeletal injuries (Table 1). Research that supports the direct use of MSC (without in vitro differentiation into tissue-specific cells) will also be reported. Based on accruing evidence that the natural healing mechanism involves the recruitment of MSC and their subsequent reparative actions at the site of injury, as well as documented therapeutic response after the exogenous administration of MSC, the feasibility of the emerging strategy of instant stem-cell therapy will be proposed.

Section snippets

Mobilization and homing of MSC

MSC are non-haematopoietic stromal cells that were first isolated from bone marrow and subsequently from other adult connective tissues [10]. They are a heterogeneous population of pluripotent progenitor cells that possess the capacity to differentiate into mesodermal and non-mesodermal cell lineages including osteocytes, chondrocytes, adipocytes, myocytes, cardiomyocytes, fibroblasts, myofibroblasts, epithelial cells and neurons [5]. MSC may be derived from bone marrow or other tissues and

Factors governing MSC migration

The exact mechanism by which MSC are mobilized into the circulation, undergo recruitment and transmigrate across the endothelium is not yet fully elucidated. However, it is probable that injured tissue expresses specific receptors or ligands to facilitate trafficking, adhesion and infiltration of MSC to the site of injury, similar to the recruitment of leukocytes to sites of inflammation [43]. The well-characterized model of leukocyte migration, together with studies on haematopoietic cell

Bone

Fracture healing is a complex regenerative process that is initiated in response to injury and is characterized by a well-orchestrated series of biological events. Unlike other tissues that undergo repair by the formation of a poorly organized scar, bone is regenerated and pre-fracture tissue properties are largely regained [72]. From a classic histological perspective, fracture healing has been categorized into primary fracture healing and secondary fracture healing [72]. Primary healing or

Cartilage

Articular cartilage is a tissue with virtually no intrinsic reparative capacity as the cells within cartilage, the chondrocytes, have low mitotic potential in vivo [22], are isolated in their lacunae, adapted to a low metabolic rate and obtain functional information only through mechanical loading and diffusible humoral factors. As such, upon injury, these cells may not be able to sense the problem, are unable to migrate out of their territory through the dense matrix to fill the defect and are

Skeletal muscle

Skeletal muscle degeneration can result due to direct injury such as crushing, cutting, puncturing or freezing, ischemia, direct application of local anaesthetics, exhaustive exercises or neuromuscular diseases [125]. At present, treatment options are dependent on the intrinsic self-healing properties of the injured muscle [37]. Skeletal muscles are capable of extensive regeneration. According to Bodine-Fowler [125], the regeneration sequence is as follows: damage to muscle or fiber, intrinsic

Concentrating bone marrow – derived MSC for therapy

Evidence presented thus far supports the hypothesis of MSC mobilization, homing and recruitment, triggered by musculoskeletal injury - a phenomenon that is likely a part of the natural reparative response. It is postulated that stimulatory factors are released by the remote injured tissue which result in mobilization of MSC from their storage niche in the bone marrow into the circulation. These circulating MSC home to the site of injury; certain molecules presented on the endothelium leads to

Conclusion

Injury is believed to trigger the mobilization of MSC into the circulation, and these cells contribute to healing by homing to the damaged tissues in a mechanism yet elucidated. These MSC undergo differentiation and/or are involved in cytokine production upon arrival at the target tissue [18]. Such a response is thought to be an inherent one that can potentially be augmented by enhancing the endogenous MSC pool with exogenously administered MSC. Studies have demonstrated that the

Acknowledgements

Dr. Goodman’s contribution has been supported in part by NIH grant R01AR55650 from NIAMS at NIH and the Ellenburg Chair in Surgery at Stanford University. We also wish to acknowledge Mr. Anthony Yong, for his assistance in literature search and compilation of bibliographic data.

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