Role of Mesenchymal Stem Cells in Bone Regenerative Medicine: What Is the Evidence?

Healing and regeneration of bone injuries, particularly those that are associated with large bone defects, are a complicated process. There is growing interest in the application of osteoinductive and osteogenic growth factors and mesenchymal stem cells (MSCs) in order to significantly improve bone repair and regeneration. MSCs are multipotent stromal stem cells that can be harvested from many different sources and differentiated into a variety of cell types, such as preosteogenic chondroblasts and osteoblasts. The effectiveness of MSC therapy is dependent on several factors, including the differentiating state of the MSCs at the time of application, the method of their delivery, the concentration of MSCs per injection, the vehicle used, and the nature and extent of injury, for example. Tissue engineering and regenerative medicine, together with genetic engineering and gene therapy, are advanced options that may have the potential to improve the outcome of cell therapy. Although several in vitro and in vivo investigations have suggested the potential roles of MSCs in bone repair and regeneration, the mechanism of MSC therapy in bone repair has not been fully elucidated, the efficacy of MSC therapy has not been strongly proven in clinical trials, and several controversies exist, making it difficult to draw conclusions from the results. In this review, we update the recent advances in the mechanisms of MSC action and the delivery approaches in bone regenerative medicine. We will also review the most recent clinical trials to find out how MSCs may be beneficial for treating bone defects.

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Adipose-derived stem cells: a review of osteogenesis differentiation

Folia Biologica et Oecologica ◽

10.1515/fobio-2016-0004 ◽

2016 ◽

Vol 12 ◽

pp. 38-47 ◽

Cited By ~ 3

Author(s):

Aleksandra Skubis ◽

Bartosz Sikora ◽

Nikola Zmarzły ◽

Emilia Wojdas ◽

Urszula Mazurek

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Regenerative Medicine ◽

Bone Tissue ◽

Tissue Regeneration ◽

Cell Types ◽

Bone Tissue Regeneration ◽

Adipose Derived Stem Cells

This review article provides an overview on adipose-derived stem cells (ADSCs) for implications in bone tissue regeneration. Firstly this article focuses on mesenchymal stem cells (MSCs) which are object of interest in regenerative medicine. Stem cells have unlimited potential for self-renewal and develop into various cell types. They are used for many therapies such as bone tissue regeneration. Adipose tissue is one of the main sources of mesenchymal stem cells (MSCs). Regenerative medicine intends to differentiate ADSC along specific lineage pathways to effect repair of damaged or failing organs. For further clinical applications it is necessary to understand mechanisms involved in ADSCs proliferation and differentiation. Second part of manuscript based on osteogenesis differentiation of stem cells. Bones are highly regenerative organs but there are still many problems with therapy of large bone defects. Sometimes there is necessary to make a replacement or expansion new bone tissue. Stem cells might be a good solution for this especially ADSCs which manage differentiate into osteoblast in in vitro and in vivo conditions.

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A comparative in vitro and in vivo study of osteogenicity by using two biomaterials and two human mesenchymal stem cell subtypes

10.1101/2021.07.17.452782 ◽

2021 ◽

Author(s):

Lucile Fievet ◽

Nicolas Serratrice ◽

Benedicte Brulin ◽

Laurent Giraudo ◽

Julie Veran ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Bone Repair ◽

Transcript Level ◽

Cell Types ◽

Human Mesenchymal Stem Cell ◽

In Vivo Experiments

Bone repair induced by stem cells and biomaterials may represent an alternative to autologous bone grafting. Here, we compared the efficiency of two biomaterials - biphasic calcium phosphate (BCP) and bioactive glass (BG) - when loaded with either adult bone marrow mesenchymal stem cells (BM-MSCs) or newborn nasal ecto-mesenchymal stem cells (NE-MSCs), the latter being collected for further repair of lip cleft-associated bone loss. Both cell types display the typical stem cell surface markers CD73+/CD90+/CD105+/nestin, and exhibit the MSC-associated osteogenic, chondrogenic and adipogenic multipotency. NE-MSCs produce less collagen and alkaline phosphatase than BM-MSCs. At the transcript level, NE-MSCs express more abundantly three genes coding for bone sialoprotein, osteocalcin and osteopontin, while BM-MSCs produce extra copies of RUNX2. BM-MSCs and NE-MSCs adhere and survive on BCP and BG. In vivo experiments reveal that bone formation is only observed with BM-MSCs transplanted on BCP biomaterial.

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Regeneration of Bone Defects Using Bioactive Glass Combined with Adipose-derived Mesenchymal Stem Cells. An experimental in vivo study

Revista de Chimie ◽

10.37358/rc.19.6.7259 ◽

2019 ◽

Vol 70 (6) ◽

pp. 1983-1987

Author(s):

Cristian Trambitas ◽

Anca Maria Pop ◽

Alina Dia Trambitas Miron ◽

Dorin Constantin Dorobantu ◽

Flaviu Tabaran ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bioactive Glass ◽

Bone Repair ◽

Bone Defects ◽

Calvarial Bone ◽

Specific Protocol ◽

Repair Mechanisms ◽

Male Wistar Rats

Large bone defects are a medical concern as these are often unable to heal spontaneously, based on the host bone repair mechanisms. In their treatment, bone tissue engineering techniques represent a promising approach by providing a guide for osseous regeneration. As bioactive glasses proved to have osteoconductive and osteoinductive properties, the aim of our study was to evaluate by histologic examination, the differences in the healing of critical-sized calvarial bone defects filled with bioactive glass combined with adipose-derived mesenchymal stem cells, compared to negative controls. We used 16 male Wistar rats subjected to a specific protocol based on which 2 calvarial bone defects were created in each animal, one was filled with Bon Alive S53P4 bioactive glass and adipose-derived stem cells and the other one was considered control. At intervals of one week during the following month, the animals were euthanized and the specimens from bone defects were histologically examined and compared. The results showed that this biomaterial was biocompatible and the first signs of osseous healing appeared in the third week. Bone Alive S53P4 bioactive glass could be an excellent bone substitute, reducing the need of bone grafts.

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Research Status of Mesenchymal Stem Cells in Liver Transplantation

Cell Transplantation ◽

10.1177/0963689719874786 ◽

2019 ◽

Vol 28 (12) ◽

pp. 1490-1506 ◽

Cited By ~ 2

Author(s):

Yu You ◽

Di-guang Wen ◽

Jian-ping Gong ◽

Zuo-jin Liu

Keyword(s):

Stem Cells ◽

Liver Transplantation ◽

Clinical Trials ◽

Mesenchymal Stem Cells ◽

In Vivo Studies ◽

Cell Contact ◽

Clinical Effects ◽

Clinical Safety

Liver transplantation has been deemed the best choice for end-stage liver disease patients but immune rejection after surgery is still a serious problem. Patients have to take immunosuppressive drugs for a long time after liver transplantation, and this often leads to many side effects. Mesenchymal stem cells (MSCs) gradually became of interest to researchers because of their powerful immunomodulatory effects. In the past, a large number of in vitro and in vivo studies have demonstrated the great potential of MSCs for participation in posttransplant immunomodulation. In addition, MSCs also have properties that may potentially benefit patients undergoing liver transplantation. This article aims to provide an overview of the current understanding of the immunomodulation achieved by the application of MSCs in liver transplantation, to discuss the problems that may be encountered when using MSCs in clinical practice, and to describe some of the underlying capabilities of MSCs in liver transplantation. Cell–cell contact, soluble molecules, and exosomes have been suggested to be critical approaches to MSCs’ immunoregulation in vitro; however, the exact mechanism, especially in vivo, is still unclear. In recent years, the clinical safety of MSCs has been proven by a series of clinical trials. The obstacles to the clinical application of MSCs are decreasing, but large sample clinical trials involving MSCs are still needed to further study their clinical effects.

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Mesenchymal Stem Cells as a Promising Cell Source for Integration in Novel In Vitro Models

Biomolecules ◽

10.3390/biom10091306 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1306

Author(s):

Ann-Kristin Afflerbach ◽

Mark D. Kiri ◽

Tahir Detinis ◽

Ben M. Maoz

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cell Types ◽

In Vitro Models ◽

Cell Source ◽

Fundamental Research ◽

Multiple Cell ◽

Vitro Model

The human-relevance of an in vitro model is dependent on two main factors—(i) an appropriate human cell source and (ii) a modeling platform that recapitulates human in vivo conditions. Recent years have brought substantial advancements in both these aspects. In particular, mesenchymal stem cells (MSCs) have emerged as a promising cell source, as these cells can differentiate into multiple cell types, yet do not raise the ethical and practical concerns associated with other types of stem cells. In turn, advanced bioengineered in vitro models such as microfluidics, Organs-on-a-Chip, scaffolds, bioprinting and organoids are bringing researchers ever closer to mimicking complex in vivo environments, thereby overcoming some of the limitations of traditional 2D cell cultures. This review covers each of these advancements separately and discusses how the integration of MSCs into novel in vitro platforms may contribute enormously to clinical and fundamental research.

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Human Adipose-Derived Mesenchymal Stem Cells-Incorporated Silk Fibroin as a Potential Bio-Scaffold in Guiding Bone Regeneration

Polymers ◽

10.3390/polym12040853 ◽

2020 ◽

Vol 12 (4) ◽

pp. 853 ◽

Cited By ~ 1

Author(s):

Dewi Sartika ◽

Chih-Hsin Wang ◽

Ding-Han Wang ◽

Juin-Hong Cherng ◽

Shu-Jen Chang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Regeneration ◽

Osteogenic Differentiation ◽

Silk Fibroin ◽

Bone Repair ◽

Matrix Deposition ◽

Calvarial Defects

Recently, stem cell-based bone tissue engineering (BTE) has been recognized as a preferable and clinically significant strategy for bone repair. In this study, a pure 3D silk fibroin (SF) scaffold was fabricated as a BTE material using a lyophilization method. We aimed to investigate the efficacy of the SF scaffold with and without seeded human adipose-derived mesenchymal stem cells (hASCs) in facilitating bone regeneration. The effectiveness of the SF-hASCs scaffold was evaluated based on physical characterization, biocompatibility, osteogenic differentiation in vitro, and bone regeneration in critical rat calvarial defects in vivo. The SF scaffold demonstrated superior biocompatibility and significantly promoted osteogenic differentiation of hASCs in vitro. At six and twelve weeks postimplantation, micro-CT showed no statistical difference in new bone formation amongst all groups. However, histological staining results revealed that the SF-hASCs scaffold exhibited a better bone extracellular matrix deposition in the defect regions compared to other groups. Immunohistochemical staining confirmed this result; expression of osteoblast-related genes (BMP-2, COL1a1, and OCN) with the SF-hASCs scaffold treatment was remarkably positive, indicating their ability to achieve effective bone remodeling. Thus, these findings demonstrate that SF can serve as a potential carrier for stem cells, to be used as an osteoconductive bioscaffold for BTE applications.

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Bone Defect Repair Using a Bone Substitute Supported by Mesenchymal Stem Cells Derived from the Umbilical Cord

Stem Cells International ◽

10.1155/2020/1321283 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15 ◽

Cited By ~ 1

Author(s):

Michal Kosinski ◽

Anna Figiel-Dabrowska ◽

Wioletta Lech ◽

Lukasz Wieprzowski ◽

Ryszard Strzalkowski ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Bone Defect ◽

Bone Substitute ◽

Bone Defects ◽

Bone Transplantation ◽

Congenital Defects

Objective. Bone defects or atrophy may arise as a consequence of injury, inflammation of various etiologies, and neoplastic or traumatic processes or as a result of surgical procedures. Sometimes the regeneration process of bone loss is impaired, significantly slowed down, or does not occur, e.g., in congenital defects. For the bone defect reconstruction, a piece of the removed bone from ala of ilium or bone transplantation from a decedent is used. Replacement of the autologous or allogenic source of the bone-by-bone substitute could reduce the number of surgeries and time in the pharmacological coma during the reconstruction of the bone defect. Application of mesenchymal stem cells in the reconstruction surgery may have positive influence on tissue regeneration by secretion of angiogenic factors, recruitment of other MSCs, or differentiation into osteoblasts. Materials and Methods. Mesenchymal stem cells derived from the umbilical cord (Wharton’s jelly (WJ-MSC)) were cultured in GMP-grade DMEM low glucose supplemented with heparin, 10% platelet lysate, glucose, and antibiotics. In vitro WJ-MSCs were seeded on the bone substitute Bio-Oss Collagen® and cultured in the StemPro® Osteogenesis Differentiation Kit. During the culture on the 1st, 7th, 14th, and 21st day (day in vitro (DIV)), we analyzed viability (confocal microscopy) and adhesion capability (electron microscopy) of WJ-MSC on Bio-Oss scaffolds, gene expression (qPCR), and secretion of proteins (Luminex). In vivo Bio-Oss® scaffolds with WJ-MSC were transplanted to trepanation holes in the cranium to obtain their overgrowth. The computed tomography was performed 7, 14, and 21 days after surgery to assess the regeneration. Results. The Bio-Oss® scaffold provides a favourable environment for WJ-MSC survival. WJ-MSCs in osteodifferentiation medium are able to attach and proliferate on Bio-Oss® scaffolds. Results obtained from qPCR and Luminex® indicate that WJ-MSCs possess the ability to differentiate into osteoblast-like cells and may induce osteoclastogenesis, angiogenesis, and mobilization of host MSCs. In animal studies, WJ-MSCs seeded on Bio-Oss® increased the scaffold integration with host bone and changed their morphology to osteoblast-like cells. Conclusions. The presented construct consisted of Bio-Oss®, the scaffold with high flexibility and plasticity, approved for clinical use with seeded immunologically privileged WJ-MSC which may be considered reconstructive therapy in bone defects.

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OSTEOIMMUNOLOGICAL IMPLICATIONS IN REGENERATIVE MEDICINE: CROSS-TALK BETWEEN MESENCHYMAL STEM CELLS AND IMMUNE CELLS

Journal of Musculoskeletal Research ◽

10.1142/s0218957721400017 ◽

2021 ◽

pp. 2140001

Author(s):

Alden Davis ◽

Robert E. Guldberg ◽

Rebekah M. Samsonraj

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Immune System ◽

T Cell ◽

Regenerative Medicine ◽

Cross Talk ◽

Immune Cells ◽

Bone Repair ◽

Bone Fractures ◽

Cell Types

Bone fractures are one of the most common orthopedic cases, yet strategies to resolve excessive inflammation and non-unions still lack satisfactory treatment methods owing to the complex fracture microenvironment, as well as the interactions between the plethora of cell types involved. Fracture is a highly inflammatory process which involves the recruitment of various immune cells which in turn release various cytokines and growth factors to perpetuate inflammation and eventually healing resolution. Osteoimmunology is an interdisciplinary field investigating the extensive interactions between the immune system and skeletal system. Mesenchymal stem cells (MSCs) are resident in almost every adult tissue and are responsible for initiating reparative cascades in the event of injury. A key aspect of MSCs is their role as trophic mediators, secreting a milieu of signaling as well as immunomodulatory cytokines that play important roles in tissue regeneration. This paracrine signaling polarizes macrophages into their anti-inflammatory M2 phenotype, activates osteoblasts, inhibits osteoclasts, as well as suppresses conventional T cell proliferation and promotes regulatory T cell (Treg) proliferation. MSCs have been shown to resolve inflammation whilst also supporting osteogenesis; for these reasons, they are considered promising candidates for cellular therapies to treat musculoskeletal pathologies. Through pretreatment and genetic modifications, MSCs can be predisposed to release specific molecules that can modulate the microenvironment and regulate the activity of the immune system towards enhancing bone repair. By understanding the cross-talk between MSCs and the immune system in bone physiology, more targeted therapies directed towards specific cells and discrete signaling molecules become possible that may allow for expedited healing and improved standard of care in orthopedics. In this review, we discuss the interplay between immune cells and MSCs and the potential ways to harness this cross-talk to improve regenerative medicine strategies.

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Repair of bone defects with prefabricated vascularized bone grafts and double-labeled bone marrow-derived mesenchymal stem cells in a rat model

Scientific Reports ◽

10.1038/srep39431 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 5

Author(s):

Xiao-Rui Jiang ◽

Hui-Ying Yang ◽

Xin-Xin Zhang ◽

Guo-Dong Lin ◽

Yong-Chun Meng ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Vascular Bundle ◽

Bone Defects ◽

Group A ◽

Group D ◽

Vascularized Bone

Abstract This study aims to investigate the repair of bone defects with prefabricated vascularized bone grafts and double-labeled bone marrow-derived mesenchymal stem cells (BMSCs) in a rat model. BMSCs were separated from rat bone marrow. LTR-CMVpro-RFP and LTR-CMVpro-GFP were transfected into the BMSCs for in vitro and in vivo tracking. BMSCs-RFP and BMSCs-GFP were induced into endothelial progenitor cells (EPCs) and osteoblasts (OBs). Rats were divided into five groups: Group A: in vitro prefabrication with EPCs-RFP + in vivo prefabrication with arteriovenous vascular bundle + secondary OBs-GFP implantation; Group B: in vitro prefabrication with EPCs-RFP + secondary OBs-GFP implantation; Group C: in vivo prefabrication with arteriovenous vascular bundle + secondary OBs-GFP implantation; Group D: implantation of EPCs-RFP + implantation of with arteriovenous vascular bundle + simultaneous OBs-GFP implantation; Group E: demineralized bone matrix (DBM) grafts (blank control). Among five groups, Group A had the fastest bone regeneration and repair, and the regenerated bone highly resembled normal bone tissues; Group D also had fast bone repair, but the repair was slightly slower than Group A. Therefore, in vitro prefabrication with EPCs-RFP plus in vivo prefabrication with arteriovenous vascular bundle and secondary OBs-GFP implantation could be the best treatment for bone defect.

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Bone Marrow-Derived NCS-01 Cells Advance a Novel Cell-Based Therapy for Stroke

International Journal of Molecular Sciences ◽

10.3390/ijms21082845 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2845 ◽

Cited By ~ 1

Author(s):

John Brown ◽

You Jeong Park ◽

Jea-Young Lee ◽

Thomas N. Chase ◽

Minako Koga ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Clinical Trials ◽

Mesenchymal Stem Cells ◽

Infarct Volume ◽

Glucose Deprivation ◽

Preclinical Research ◽

Cell Based Therapy

Human mesenchymal stem cells have been explored for their application in cell-based therapies targeting stroke. Identifying cell lines that stand as safe, accessible, and effective for transplantation, while optimizing dosage, timing, and method of delivery remain critical translational steps towards clinical trials. Preclinical studies using bone marrow-derived NCS-01 cells show the cells’ ability to confer functional recovery in ischemic stroke. Coculturing primary rat cortical cells or human neural progenitor cells with NCS-01 cells protects against oxygen-glucose deprivation. In the rodent middle cerebral artery occlusion model, intracarotid artery administration of NCS-01 cells demonstrate greater efficacy than other mesenchymal stem cells (MSCs) at improving motor and neurological function, as well as reducing infarct volume and peri-infarct cell loss. NCS-01 cells secrete therapeutic factors, including basic fibroblast growth factor and interleukin-6, while also demonstrating a potentially novel mechanism of extending filopodia towards the site of injury. In this review, we discuss recent preclinical advancements using in vitro and in vivo ischemia models that support the transplantation of NCS-01 in human stroke trials. These results, coupled with the recommendations put forth by the consortium of Stem cell Therapeutics as an Emerging Paradigm for Stroke (STEPS), highlight a framework for conducting preclinical research with the ultimate goal of initiating clinical trials.

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