ReviewStem cell homing in musculoskeletal injury
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.
References (150)
- et al.
A perivascular origin for mesenchymal stem cells in multiple human organs
Cell Stem Cell
(2008) - et al.
Bloodstream cells phenotypically identical to human mesenchymal bone marrow stem cells circulate in large amounts under the influence of acute large skin damage: new evidence for their use in regenerative medicine
Transpl Proc
(2006) - et al.
Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats
J Neurol Sci
(2001) - et al.
A tissue engineering approach to bone repair in large animal models and in clinical practice
Biomaterials
(2007) - et al.
Mesenchymal stem cells as a potential pool for cartilage tissue engineering
Ann Anat
(2008) - et al.
Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells
Osteoarthritis Cartilage
(2007) - et al.
Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees
Osteoarthritis Cartilage
(2002) - et al.
Repair of full-thickness cartilage defects with cells of different origin in a rabbit model
Arthroscopy
(2007) - et al.
Mesenchymal stem cells for bone, cartilage, tendon and skeletal muscle repair
Bone
(2006) - et al.
Biological considerations of mesenchymal stem cells and endothelial progenitor cells
Injury
(2008)
Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement
Cytotherapy
Mesenchymal stem cell homing: the devil is in the details
Cell Stem Cell
Homing and engraftment of progenitor cells: a prerequisite for cell therapy
J Mol Cell Cardiol
How do stem cells find their way home?
Blood
Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells
Blood
Leukocyte–endothelial cell recognition: three (or more) steps to specificity and diversity
Cell
Stem cell trafficking in tissue development, growth, and disease
Cell
Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets
Blood
A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow
Blood
Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance
Mol Ther
Insulin-like growth factor 1 enhances the migratory capacity of mesenchymal stem cells
Biochem Biophys Res Commun
MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines
Blood
Galanin is highly expressed in bone marrow mesenchymal stem cells and facilitates migration of cells both in vitro and in vivo
Biochem Biophys Res Commun
Ischemic cerebral tissue and MCP-1 enhance rat bone marrow stromal cell migration in interface culture
Exp Hematol
Mesenchymal stem cells transmigrate over the endothelial barrier
Eur J Cell Biol
Overview of the fracture healing cascade
Injury
Molecular aspects of fracture healing: which are the important molecules?
Injury
The role of mesenchymal stem cells in maintenance and repair of bone
Injury
Current concepts of molecular aspects of bone healing
Injury
Systemic recruitment of osteoblastic cells in fracture healing
J Orthop Res
Transplanted bone marrow cells localize to fracture callus in a mouse model
J Orthop Res
Percutaneous bone marrow grafting for the treatment of tibial non-union
Injury
Role of mesenchymal stem cells in regenerative medicine: application to bone and cartilage repair
Expert Opin Biol Ther
One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues
Proc Natl Acad Sci U S A
Clinical applications of musculoskeletal tissue engineering
Br Med Bull
In search of the in vivo identity of mesenchymal stem cells
Stem Cells
Trafficking and differentiation of mesenchymal stem cells
J Cell Biochem
Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo
J Cell Physiol
Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp
J Bone Miner Res
Adult mesenchymal stem cells
The Stem Cell Research Community
StemBook
Growing bone and cartilage. The role of mesenchymal stem cells
J Bone Jt Surg Br
Changes in circulating mesenchymal stem cells, stem cell homing factor, and vascular growth factors in patients with acute ST elevation myocardial infarction treated with primary percutaneous coronary intervention
Heart
Regenerative effects of transplanted mesenchymal stem cells in fracture healing
Stem Cells
Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects
Proc Natl Acad Sci U S A
Migration of mesenchymal stem cells to heart allografts during chronic rejection
Transplantation
Recent advances into the understanding of mesenchymal stem cell trafficking
Br J Haematol
Stem cell-mediated accelerated bone healing observed with in vivo molecular and small animal imaging technologies in a model of skeletal injury
J Orthop Res
Adult mesenchymal stem cells for tissue engineering versus regenerative medicine
J Cell Physiol
Mesenchymal cell-based repair of large, full-thickness defects of articular cartilage
J Bone Jt Surg Am
Injectable mesenchymal stem cell therapy for large cartilage defects – a porcine model
Stem Cells
Cited by (177)
Synthetic peptides of IL-1Ra and HSP70 have anti-inflammatory activity on human primary monocytes and macrophages: Potential treatments for inflammatory diseases
2024, Nanomedicine: Nanotechnology, Biology, and MedicineStem cells from human exfoliated deciduous teeth relieves Alzheimer's disease symptoms in SAMP8 mice by up-regulating the PPARγ pathway
2022, Biomedicine and PharmacotherapyEctopic models recapitulating morphological and functional features of articular cartilage
2021, Annals of AnatomyA multifaceted biomimetic interface to improve the longevity of orthopedic implants
2020, Acta Biomaterialia