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21 December 2020

Clinical Application of Bone Marrow Mesenchymal Stem/Stromal Cells to Repair Skeletal Tissue

and
1
Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5001, Australia
2
Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci.2020, 21(24), 9759;https://doi.org/10.3390/ijms21249759
This article belongs to the Special Issue Cell Therapy Approaches for Bone and Cartilage Regeneration
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Abstract

There has been an escalation in reports over the last decade examining the efficacy of bone marrow derived mesenchymal stem/stromal cells (BMSC) in bone tissue engineering and regenerative medicine-based applications. The multipotent differentiation potential, myelosupportive capacity, anti-inflammatory and immune-modulatory properties of BMSC underpins their versatile nature as therapeutic agents. This review addresses the current limitations and challenges of exogenous autologous and allogeneic BMSC based regenerative skeletal therapies in combination with bioactive molecules, cellular derivatives, genetic manipulation, biocompatible hydrogels, solid and composite scaffolds. The review highlights the current approaches and recent developments in utilizing endogenous BMSC activation or exogenous BMSC for the repair of long bone and vertebrae fractures due to osteoporosis or trauma. Current advances employing BMSC based therapies for bone regeneration of craniofacial defects is also discussed. Moreover, this review discusses the latest developments utilizing BMSC therapies in the preclinical and clinical settings, including the treatment of bone related diseases such as Osteogenesis Imperfecta.

1. Therapeutic Potential of Bone Marrow Mesenchymal Stem Cells

Bone mineral is composed of inorganic (hydroxyapatite crystals) and organic components (predominantly a collagen type 1 dependent extracellular matrix). The microenvironment within the bone is also complex, consisting of multiple cell types. These include the stromal lineage, of osteogenic (osteogenic progenitors, osteoblasts, bone lining cells and osteocytes), adipogenic and chondrogenic derivatives, and the hematopoietic lineage of the erythroid, myeloid and lymphoid derivatives. The microenvironment also consists of endothelial, perivascular, and neural populations that collectively maintain skeletal integrity and assist in skeletal repair following injury. These cell types interact with bone marrow mesenchymal stem/stromal cells (BMSC) to maintain mechanical strength and skeletal integrity by continuously remodeling the skeleton throughout life [1,2,3,4,5,6]. The physiological process of primary bone healing, where no callus is formed, consists of the initial inflammatory phase, followed by the infiltration of monocytic derived pre-osteoclasts to the injury site. The pre-osteoclasts mature forming multinucleated osteoclasts resorbing the bone matrix. This process is followed by the reversal phase where BMSC and osteoprogenitors are sequestered, localize, integrate and undergo osteogenic differentiation, synthesizing bone matrix (osteoid) which is subsequently mineralized [7]. Secondary bone healing following fracture requires distinct highly coordinated yet overlapping physiological process. The repair begins with the inflammatory phase, where necrotic tissue is removed and angiogenesis is initiated. This is followed by the infiltration of mesenchymal stem cells (MSC)/progenitors that facilitate endochondral ossification, stabilizing the fracture site through the formation of a calcified cartilage matrix. This soft callus is subsequently resorbed by chondroclasts, allowing for the formation of a hard callus; a woven mineralized matrix synthesized by osteoblasts. The subsequent remodeling phase utilizes osteoclasts to resorb the immature woven bone slowly replacing it with osteoblasts derived lamellar bone [8,9,10]. These processes of bone healing are spatially and temporally regulated and rely on numerous cellular and molecular interaction [10,11].
In particular circumstances this bone healing process is impaired and requires assistance, this includes but is not limited to non-union fractures or critical sized bone defects, infection, musculoskeletal diseases such as osteoporosis; osteosarcomas, osteomyelitis, congenital disorders such as osteopetrosis, osteogenesis imperfecta, cleft lip or palate, in addition to rheumatoid arthritis and osteoarthritis. The clear medical need to assist in this skeletal repair has underpinned the development of novel approaches and refinement of existing approaches to improve musculoskeletal tissue engineering strategies.
BMSC display many favorable characteristics for regenerative therapy, which have been wildly described including their multipotency, anti-inflammatory and immune-modulatory properties [12,13]. This stem cell population also has the ability to support hematopoiesis and stimulate angiogenesis. Furthermore, the release of paracrine factors by BMSC influences the surrounding microenvironment, which is a characteristic of particular interest for organ repair [14]. It has been shown that while BMSC may not engraft with high efficiency following transplantation, they can support the survival of the surrounding tissue through the release of these paracrine factors [15,16]. Due to these therapeutically desirable properties, BMSC have been utilized and investigated in the treatment of a range of diseases including cardiac, lung, neural, hematopoietic, graft-versus-host disease, in addition to tendon, ligament and musculoskeletal tissue repair [17].
In 2006 The International Society for Cellular Therapy defined human derived BMSC to consist of the following criteria (1) isolated cells are plastic adherent in culture, (2) these cells express cluster of differentiation (CD) 73 CD73, CD90, and CD105 in greater than 95% of the cell population, (3) greater than 95% of the cells lack the expression of CD14 or CD11b, CD79a or CD19, CD34, CD45, and Human leukocyte antigen (HLA)-DR, and (4) the cultured BMSC have the ability to differentiate into osteoblasts, adipocytes and chondroblasts [18]. These criteria, while important are limited and lack indices for stemness. A number of additional cell surface markers have since been identified which isolate clonogenic BMSC that are able to self-renew, support hematopoiesis and possess multi-lineage differentiation potential. These include STRO-1, CD146, CD106, platelet-derived growth factor receptor (PDGF-R), epidermal growth factor receptor (EGF-R), insulin-like growth factor receptor (IGF-R), CD49a/CD29, nerve growth factor receptor (NGF-R), CD271, CD44, [19,20,21,22,23,24,25,26,27]. In addition to their capacity to form bone, cartilage and adipose tissue, BMSC have been shown to differentiate into tendon, myogenic and neural cells in vitro and in some circumstances in vivo in response to the surrounding environmental factors [14]. While BMSC were initially isolated from the bone marrow, MSC-like populations have subsequently been identified in other tissues including adipose tissue, dental pulp, referred to as dental pulp stem cells (DPSC), periodontal ligament, perivasculature, umbilical cord, placenta, synovial membrane [21,25,28,29,30,31,32]. These MSC-like populations play an important role in tissue engineering and regenerative therapy, however the present review will focus predominantly on BMSC unless otherwise stated.

2. Skeletal Tissue Regeneration—Advancements over the Last Decade

Over the past decade a greater understanding has emerged of the capabilities of BMSC in skeletal regeneration with mainly pre-clinical studies and a handful of clinical studies underway, addressing the potential of using BMSC therapy in conjunction with ceramic, biodegradable, synthetic and or matrix scaffolds for the treatment of musculoskeletal tissue repair [3]). The ever expanding development of BMSC based therapies, for the treatment and repair of musculoskeletal tissue is evidenced by numerous human clinical studies addressing different bone regeneration applications (Table 1 and Table 2), as well as animal studies seeking to improve veterinary practice [33,34].
Table 1. Clinical Trials in Fracture Repair. Search criteria in ClinicalTrails.gov: BMSC and bone fracture, scaffold and bone fracture, stem cells and scaffold and bone fracture. Terminated, suspended and withdrawn trials and cartilage related trials have been removed from the table.
Table 2. Clinical Trials in Bone Regeneration. Search criteria in ClinicalTrails.gov: BMSC and bone regeneration, scaffold and bone regeneration, stem cells and scaffold and bone regeneration. Terminated trials, fracture related trials and cartilage related trials removed from the table.
Whilst there are challenges associated with the generation of diverse tissue engineering strategies, considerable advances have been made to repair and regenerate skeletal tissue using numerous approaches, which are continuing to be developed and improved with particular attention given to elucidating the mechanisms by which regeneration is facilitated [35,36,37,38]. These include choosing the right source of the stem cell, whether autologous or allogeneic; how these stem cells are localized to the injury site directly or indirectly through migration; and whether endogenous BMSC are recruited to participate in the regeneration process [39,40]. The timing of administrating exogenous BMSC is also critical with respect to the hematoma and inflammatory response to achieve the greatest bone repair [5,41]. Importantly, efforts are being made to determine how BMSC are subsequently integrated to form the correct cell configuration and able to differentiate, repair and recapitulate the functional skeletal tissue and how mechanical loading is exerted upon the MSC engineered bone [42]. Another consideration is to improve/restore or modulate the diseased or disrupted microenvironment prior to the commencement of the regenerative therapy, to ensure greater efficacy in skeletal repair [43]. Furthermore, a permissive vascular environment is imperative for bone formation, where vascular supply assists in bone regeneration by mitigating hypoxic conditions and necrosis within the scaffold, in addition to the strong coupling between angiogenesis and osteogenesis. The structure of the cortical bone, the trabecular bone and the marrow space differ from one another, yet all need to be regenerated following non-union fracture. Numerous cell types also need to be supported within these diverse structures. For this to occur the distinctive and specific fabrication of biomaterials and delivery methods are required to recruit endogenous BMSC or deliver exogenous BMSC.

Delivery Modes of Bioactive Signals and/or BMSC

The methods developed to recruit endogenous BMSC and deliver exogenous BMSC systemically or locally (Figure 1) include cell-free strategies, magnetic cell labeling and tissue specific targeting, aptamer-nanoparticles, small bioactive molecules, injectable agents, the use of platelet-rich plasma (PRP) or bone marrow aspirates, BMSC secreted exosomes, and bio-engineered scaffold approaches, including three dimensional (3D) bioprinting (bioinks) [43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58].
Figure 1. Schematic representation of the current approaches to bone regeneration. Non-cell therapy approaches to bone regeneration encompass bioactive molecules cellular derivatives and hydrogels/scaffolds/implants that can interact with and regulate/influence cellular responses. Cell therapy approach comprise the delivery of exogenous cells, either autologous or allogeneic in combination with non-cell therapy approaches. Alternatively the activation of endogenous cells (stem cells, endothelial cells, hematopoietic populations and/or mesenchymal populations) through non-cell therapy approaches have been and are currently being developed to regenerate the appropriate skeletal tissue. The bioactive molecules include a range of growth factors/cytokines, small molecules/drugs, endocrines/hormones, antibiotics and nucleic acid/genetic manipulation. The cellular derivatives incorporate components that have been derived from cells within the bone, these include exosomes, conditioned media, plasma/platelet rich plasma (PRP) and aspirates from the bone marrow (BM). The hydrogels/scaffolds/implants embodies the fabrication of injectable, microbeads, nanogels, fibers, biofilms, membranes, sponges, bone grafts and solid scaffolds that are derived from either natural materials, synthetic polymers, ceramics, nanoparticles, metal alloys or composites of these components. These bio-compatible hydrogels/scaffolds are also manipulated to incorporate and deliver cells, cellular derivatives and/or bioactive molecules in a temporal and spatial manner to enrich bone regeneration.
The importance of incorporating/utilizing bioactive signals for enhanced bone regeneration has expanded considerably in recent times. These bioactive signals include growth factors, small molecules, endocrines, antibiotics and nucleic acids. The strategies developed thus far to induce endogenous BMSC infiltration and skeletal repair through the delivery of these bioactive signals include an array of diverse approaches reviewed by Dang and colleagues [55]. These include surface presentation of the bioactive signal, or preprogrammed controlled and sustained release of the bioactive signals via responsive release, due to endogenous signals or external stimuli such as temperature, pH, ultrasound, electric or magnetic field, light irradiation or biomolecules. Other developments involve gene delivery strategies, facilitated through gene transduction or transfection utilizing viral or non-viral vectors, respectively, to regulate molecular expression and cellular function, such as proliferation and osteogenic differentiation, which promote skeletal repair.
Hydrogels and scaffolds use a range of natural and synthetic materials and biopolymers to achieve bone regeneration [56,57]. Natural materials include proteins, such as collagen, gelatin, laminin, keratin, elastin, fibroin, fibrin, heparin; or polysaccharides such as hyaluronan, chitosan and alginate, while those with microbial activity including cellulose, gellan gum and dextran [58,59,60,61,62,63]. Synthetic biopolymers include poly(ethylene glycol) (PEG), polyacrylamide (PAM), plyvinyl alcohol (PVA), poly lactic acid to name a few [57,58,64,65]. Furthermore, minerals such as calcium (Ca), phosphorus (P), magnesium (Mg), potassium (K), zinc (Zn) and copper (Cu) are important in bone structure. Ceramics with structural similarity to these minerals, such as hydroxyapatite (HA), calcium phosphate (CaP), tri-calcium phosphate (TCP) have been sourced for bone regeneration [66]. However, there are distinct differences in the osteogenic promoting properties of these materials in vivo between species, which often lead to encouraging pre-clinical studies but poor human clinical outcomes [67,68]. Other ceramics including coral, bioactive glass ceramics, silicon dioxide (SiO2), zirconium oxide (ZrO2), titanium dioxide (TiO2) and metal alloys, such as titanium (Ti) and Mg have also been utilized in scaffold synthesis [63,64,65,69].
Hydrogels and scaffolds possess desirable qualities to either assist in the regeneration of bone or to provide a bone substitute [58,65,70]. Hydrogels are versatile in geometry and can be used as an injectable or for transplantation. They provide the necessary moisture required to mimic the tissue-like extracellular matrix microenvironment, while solid porous scaffolds attempt to mimic bone. Both allow for cellular induction, dynamic multi-cellular interactions, which can then lead to cellular differentiation in situ. However it has become apparent in recent years that fabrication, biocompatibility, bio-degradability and bio-integration, immunogenicity, cytotoxicity, gelation time, porosity, incorporation of metal ions, payload release profile, cellular infiltration, delivery of a vascular permissive environment, bone adhesiveness, degradation time, mechanical and anti-bacterial properties need to be considered when developing hydrogels, scaffolds or composites [70,71,72,73,74,75,76]. The natural and synthetic materials are fabricated into a range of structures including but not limited to injectable hydrogels, microbeads, nanogels, hydrogel fibers, biofilms, membranes, solid porous scaffolds or sponges. These scaffolds are prepared by microfluidics, in situ polymerization, electrostatic droplet extrusion, emulsification and coaxial air jetting, physical and chemical crosslinking, electrospinning, solvent casting and particulate leaching, gas-foaming, powder compaction, emulsion freeze-drying, thermal phase separation, laser sintering, stereolitography, and 3D printing [56,59,60].
New tissue engineering approaches are being employed to generate composite hydrogels/scaffolds combining biopolymers, materials, small molecules or cells for enriched skeletal regeneration [55,65,67]. For example, Liu and colleagues have modified the chitosan (CS) hydrogels, incorporating catechol (CA), to improve the adhesive properties of the hydrogel, and zeolitic imidazolate framework-8 nanoparticle (ZIF-8 NP), where zinc displays antibacterial properties, and contributes to angiogenesis and osteogenesis [77]. Supportive in vitro data using rat BMSC and an in vivo studies using a rat calvarial defect model demonstrated that the CA/CS hydrogel modified by ZIF-8 NP at a medium (1.2 mg) composition (CA-CS/ZM) hydrogel combined with bone graft was more stable, displayed neovascularization and osteogenesis, and enhanced bone regeneration [77]. Furthermore elastin-like proteins (ELP) and surfactants fabricating structured organofibers have recently been developed. These organofibers are strong, elastic and can be programed with molecular and protein engineering approaches and survival of BMSC. Although still at a proof-of-concept stage, this tissue engineering strategy holds great promise [78].
Studies utilizing silk fibroin, have shown promising results where this material appears to be as efficient in assisting in bone formation as commercially available collagen membranes [79]. Silk fibroins in combination with HA nanocomposite particles can be adjusted to facilitate the formation of different bone types or required regeneration period [80]. Alternatively silk fibroins have been manipulated in vitro to form biomaterial rolls resembling the appearance of osteons, which enabled not only osteogenesis of human MSC (hMSC) but also the survival and directional growth of neurite processes [81]. Other examples include the development of bioglass functionalized gelatin nanofibrous scaffolds, which promoted ectopic bone formation in rats [64], and the use of the BMSC derived extracellular matrix in combination with a 3D-printed HA scaffold to promote strong osteogenic ability and appropriate “tissue-space” structure [82]. Furthermore, researchers have also suggested bone synthesis can be improved via a biphasic dual delivery scaffold systems [83,84]. More specifically one approach used a system containing two scaffolds, one consisted of a Collagen type I hydrogel that was overlaid onto the surface of the other beta-TCP (β-TCP) scaffold. The β-TCP scaffold contained a slow release of osteogenic peptide (functionally synthesized equivalent of bone morphogenetic protein-2 (BMP-2)), while the hydrogel was loaded with a quick release angiogenic peptide (functionally synthesized equivalent of vascular endothelial growth factor (VEGF)), thus appropriately influencing both osteogenesis and angiogenesis, respectively [84]. In the preclinical setting others are investigating the multifactorial approach of utilizing hMSC in conjunction with endothelial progenitor cells cultured within a macroporous scaffold under “dynamic conditions” in a biaxial bioreactor prior to sub-cutaneous transplantation in immunocompromised mice. This study demonstrated enhancing vascularization improves bone formation both in vitro and in vivo [73]. The importance of the vasculature for bone regeneration is also supported by other studies. Where periosteum derived cells, albeit from mouse, undergo osteogenesis, these cells also contribute to various facets of vascularization. The production of VEGF promoted angiogenesis by adopting pericyte characteristics which support the vasculature [85].
Alternative approaches have provided an environment that is less likely to cause infection such as osteomyelitis. This was addressed by modifying nanoscale HA with sliver, which is known to have antimicrobial properties, and combining with an electrospun scaffolds. As a proof-of-concept study this scaffold was shown to be non-toxic to rat BMSC and improved osteogenic differentiation capacity of cultured BMSC, while significantly reducing bacterial populations [86]. Using a similar concept, ZnO/nanocarbon modified fibrous scaffolds have demonstrated osteogenic and antibacterial properties, albeit in vitro [87]. While there are still limitations with regard to the functional capacity of hydrogels and scaffolds, the unique and versatile configurations and continuous refinement in combination with BMSC treatment holds considerable promise for bone regeneration [70,74].

4. Conclusions/Summary

Whilst the use of tissue engineering for skeletal repair is a complex undertaking, it has been shown to be a feasible approach for mediating bone regeneration, through the exploitation of the multi-faceted characteristics of MSC. Over the last decade, significant advancements have been made in the field of bone tissue engineering through interdisciplinary collaborations. These advances have led to the generation of novel hydrogels and biomimetic scaffolds as cell-free delivery systems, and the use of MSC alone, their products or in combination with biomaterials and/or bioactive molecules to attain the appropriate mechanical, cellular and regenerative properties required to recapitulate bone structures. This work has made considerable headway into the clinic, with encouraging outcomes being reported for non-union fracture repair. However, further studies are still required to build on current preclinical and clinical studies in order to address limitations in facilitating tissue and site specific osseous repair. In particular, more detailed assessment is required to understand the heterogeneity of different stromal populations and their products or factors that contribute to bone synthesis. Importantly, the role of resident cell populations within the bone microenvironment, require further investigation to identify the mechanisms driving bone regeneration. It is anticipated that future advances in MSC based therapies would also benefit from the inclusion of adjuvant strategies (such as plasma products) and the manipulation of other cellular components (such as monocytes, pre-osteoclasts and endothelial cells), which help recapitulate and maintain the bone microenvironment. This could be facilitated through the use of scaffold based systems to deliver small molecules and/or genetic modified BMSC for more directed and controlled skeletal tissue regeneration.

Author Contributions

All authors contributed equally to this manuscript “Conceptualization, A.A. and S.G.; investigation, A.A. and S.G.; writing—original draft preparation, A.A.; writing—review and editing, S.G.; funding acquisition, S.G.”. All authors have read and agreed to the published version of the manuscript.

Funding

This review was funded by The National Health and Medical Research Council Australia, Project Grant APP1142954.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

3DThree dimensional
αAlpha
βBeta
BMMNCBone marrow mononuclear cells
BMPBone morphogenetic protein
BMSCBone marrow stromal/stem cells
CaCalcium
CACatechol
CA-CS/ZMCa/cs hydrogel modified by zif-8 np at a medium (1.2 mg) composition
CAGChitosan-agarose-gelatin
CaPCalcium phosphate
CDCluster of differentiation
CFNSCraniofrontonasal syndrome
CFU-FColony forming unit-fibroblast
CPCCalcium phosphate cement
CSChitosan
CSO/HChitosan oligosaccharide/heparin
CuCopper
CXCL12C-X-C Motif Chemokine Ligand 12
CXCR4C-X-C Chemokine Receptor type 4
DBBMDeproteinized bovine bone mineral
DBMDemineralized bone matrix
DPSCDental Pulp Stem Cells
ECMExtracellular matrix
EGF-REpidermal Growth Factor Receptor
ELPelastin-like proteins
FDAFood and Drug Administration
HAHydroxyapatite
hiPSChuman derived induced pluripotent stem cells
HLA-DRHuman Leukocytet Antigen-DR
hMSCHuman mesenchymal stem cells
IGFBP5Insulin-like Growth Factor Binding Protein 5
IGF-RInsulin-like Growth Factor Receptor
IL-10Interleukin 10
KPotassium
Lrg5Leucine Rich Repeat Containing G Protein-Coupled Receptor 5
MgMagnesium
NGF-RNerve Growth Factor Receptor
OIOsteogenesis Imperfecta
PPhosphorus
PAMPolyacrylamide
PDGF-RPlatelet-Derived Growth Factor Receptor
PEGPoly(ethylene glycol)
PLGAPoly Lactic-co-Glycolic Acid
PRPPlasma rich plasma
PTHParathyroid Hormone
PTH1RParathyroid Hormone 1 Receptor
PVAPlyvinyl alcohol
RANKLReceptor Activator of Nuclear Factor-Kappa B
SiO2Silicon dioxide
TCPTri-calcium phosphate
TGATherapeutic Goods Administration
TiTitanium
TiO2Titanium dioxide
TNFαTumor Necrosis Factor alpha
VEGFVascular Endothelial Growth Factor
ZAZoledronic acid
ZIF-8 NPZeolitic imidazolate framework-8 nanoparticle
ZnZinc
ZnOZinc oxide
ZrO2Zirconium oxide

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