Comparison of Bone regeneration in hADMSC Versus hUCBMSC with hBMMSC as a Reference: A Literature Review of Potential Bone Regeneration

 

Sudarmono¹, Sunardhi Widyaputra², Suhardjo Sitam³, Inne Suherna⁴, Arni D. Fitri⁵, Arif Rachman⁶*

 

ABSTRACT:

Mesenchymal stem cells (MSCs) are an important class of stem cells that can differentiate into osteoblasts, chondrocytes, and adipocytes. MSCs must express CD105, CD73, and CD90 and differentiate into osteoblasts, adipocytes, and chondroblasts. The beneficial effects of MSCs on bone remodeling are mainly provided by a paracrine effect. In bone regeneration, implanted hADMSCs secrete various osteoblast-activating factors, receptor activator of nuclear factor kappa-B ligand (RANKL), BMP-2, BMP-4, hepatocyte growth factor (HGF) and bone-related extracellular matrix proteins. The MSCs possess multipotent capabilities, paracrine, autocrine, and migration capacity to the tissue, directly initiating healing and regeneration with a specified standard. hADMSCs has demonstrated bone regenerative capabilities. DLX5 and RUNX2 as potential bone regeneration references by looking at the osteogenic cells of each source cell. The ability of hADMSC bone regeneration is higher than hUCBMSC due to the capacity of hADMSC osteogenesis which leads to bone and cartilage formation.

 

 

 

INTRODUCTION:

Tissue engineering has components consisting of cells, scaffolds, and growth factors called the triad of network engineering^1,2. Adult stem cells have more differentiation capabilities than previously estimated and are involved in regeneration and repair during soft tissue injury, bone injury, wound healing, and aging. Mesenchymal stem cells (MSCs) are an important class of stem cells that can differentiate into osteoblasts, chondrocytes, and adipocytes³. In addition, MSCs play an active role in repairing and maintaining tissue homeostasis.

 

Osteoblasts have the potential for bone regeneration where the osteoblasts have the ability to differentiate as effector cells^1,2. Stem cell therapy provides a permanent, biological solution, and regardless of their source, all stem cells, including embryonic, induced pluripotent, fetal, and adult stem cells, have some degree of potential for regenerative medicine. Recently, various MSCs including bone marrow-derived MSCs (BMDMSCs), umbilical cord blood-derived MSCs (UCB-MSCs), human umbilical cord MSCs (hUCMSCs), human adipose tissue-derived MSCs (hADMSCs), muscle-derived stem cells (MDSCs), and dental pulp stem cells (DPSCs) have been used for bone regeneration⁴.

 

The Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy defined three criteria for identifying human MSCs. First, MSCs must be plastic adherent when maintained in standard culture conditions. Second, MSCs must express CD105, CD73, and CD90, but not CD45, CD34, CD14 or CD11b, CD79a or CD19, and HLA-DR surface molecules. Third, MSCs must differentiate to osteoblasts, adipocytes, and chondroblasts in vitro^4,5,6,7,8.

 

According to their sources or characteristics, MSCs can be divided into bone marrow MSCs (BMSCs), adipose-derived MSCs (ASCs), perivascular stem cells (PSCs), induced pluripotent stem cells (iPSCs), and genetically modified MSCs⁹. However, the relative advantages of each MSCs population for bone regeneration have yet to be established5. Stem cell-based therapies that integrate tissue-engineering technologies and biomaterials science are fundamental pillars of the science of regenerative medicine¹⁰. MSCs can be obtained from several sources and are now of great interest due to their potential to differentiate into osteoblasts and chondroblasts¹¹. MSCs also display tissue reparative properties apart from anti-tumorigenic, anti-fibrotic, anti-apoptotic, anti-inflammatory, pro-angiogenic, neuroprotective, anti-bacterial and chemo-attractive effects¹².

 

HUMAN ADIPOSE-DERIVED MESENCHYMAL STEM CELLS (hADMSC):

Human Adipose-Derived Mesenchymal Stem Cells (hADMSC) is a multipotent cell that can differentiate into osteogenic, chondrogenic, and adipogenic cells^1,2. hADMSC has been investigated for the repair of myocardial infarction, allergic rhinitis, and muscular dystrophy using many animal models. hADMSC displays a higher rate of proliferation compared to human Bone Marrow Mesenchymal Stem Cell (hBMMSC). However, the proliferation rate of hADMSC is heavily dependent upon the region of the body from which the adipose tissue (AT) is derived. hADMSC proliferates faster when derived from the subcutaneous fat region than the omental fat region. Therefore, variation in the sources of hADMSC can cause inconsistencies with the results. hADMSC also differs in their differentiation potential when compared with hBMMSC.  hADMSC was able to differentiate towards the osteogenic lineage but not to the same extent as hBMMSC. However, in a different study, there was no significant differences in the osteogenic potential of MSCs derived from bone marrow (BM) and AT⁷.

 

Chondroblasts and chondrocytes are the major cellular components of cartilage tissue, along with the ECM, which makes up most of the cartilage matrix. The chondroblasts are developed from MSCs, while the ECM is produced by chondroblasts and chondrocytes. As chondroblasts mature into chondrocytes, they secrete extracellular matrix, trapping themselves within it. Inside the ECM, chondrocytes further divide into groups of 2–4 cells, forming ECM-covered lacunae. The ECM of cartilage is composed of proteoglycan molecules, which are cross-linked and contain fixed negative charges. Proteoglycans, as a component with such a specialized structure, enables the ECM to withstand various forces. Chondroblasts and chondrocytes in the cartilage tissue maintain specialized functions of the ECM by regulating synthesis and degradation¹³. MSCs derived from bone marrow are adherent to plastic, exhibit the ability to differentiate into osteoblasts, adipocytes, and chondrocytes and are CD90 positive. More importantly, they exhibit expression of CD105, CD44, and CD90 with low or negative expression of CD34 and major histocompatibility complex II (MHC-II). Differences have been noted in another study showing equine bone marrow-derived MSCs are heterogenous in MHC-II expression. Variation in expression of MHC-II is seen through multiple passages, as well. One study of adipose-derived MSCs produced mixed results, showing increased expression of CD44 with the increased number of passages in a small number of samples¹⁴. hADMSC can be easily isolated, providing an enormous number of stem cells that are vital for tissue engineering and stem cells-based therapies¹⁵. hADMSCs are stem cells derived from adipose tissues and are, thus, abundant, and have been widely used for regenerative medicine⁹.

 

Human Umbilical Cord Blood Mesenchymal Stem Cells (hUCBMSC):

Umbilical cord compartments can be used to isolate MSCs. The most widely used compartments are Wharton’s jelly (WJ), perivascular tissue, and umbilical cord blood (UCB). In vitro experiments reported that hUCBMSCs had a longer culture period, a larger scale expansion, retardation of senescence, and a higher anti-inflammation effect, but they had less osteogenic activity compared to hBMSCs. Therefore, the feasibility of hUCBMSCs as an alternative to hUCBMSCs remains controversial. Moreover, this type of cell has not been tested in vivo for promoting bone regeneration⁵. MSCs have also exhibited an ability to enhance proper ECM events during healing process. Conditioned media from hUCBMSCs have shown to inhibit the expression of matrix metalloproteinase (MMP)-1, which suggests that MSCs suppress degradation of the collagenous matrix and serve to preserve the matrix and contribute to fibroblast regeneration⁸. hUCBMSCs has gained much attention as being a potential cell source for tissue engineering and regenerative medicine¹⁰.

 

hUCBMSCs are composed of HSCs, endothelial progenitor cells, and MSCs. Similar to BM, the amount of MSCs in UCB is extremely low, making it difficult to isolate MSCs from UCB. Furthermore, the proliferation potential of hUCBMSCs has shown to be dependent on the gestational age and that the growth rate of hUCBMSCs is significantly lower at full term. However, hUCBMSCs have shown to be positive for CD73, CD90, and CD105 and can differentiate towards the adipogenic, chondrogenic, and osteogenic lineages. In a recent study, hUCBMSCs showed greater chondrogenic and osteogenic differentiation potential when compared to adult derived MSCs. Aside from the UCB, the Umbilical Cord (UC) has also been extensively studied for MSC isolation⁷. When hBMMSCs and hUCBMSCs were placed in an osteoconductive material and then transplanted subcutaneously in a severe combined immunodeficiency/beige mouse, injected hBMMSCs only formed bone, whereas injected hUCBMSCs formed both bone and cartilage⁷. hUCBMSC can be collected noninvasively and ethically, and hUCBMSCs have improved cell activity and proliferation ability, with low immunogenicity, and they do not need human leukocyte antigen (HLA) antigen matching. The incidence of posttransplant infection is lower with hUCBMSC transplants when compared with MSCs from other sources, making them an ideal source of seed cells in tissue engineering¹¹. hUCBMSCs display improved progenitor cell capacity and harbor strong differentiation potential towards mesenchymal lineages in a similar fashion as other cell source. Although therapeutic potential and biological mechanisms underlying tissue regeneration and repair of hUCBMSC in vivo remain unclear, the introduction of hUCBMSC as a therapeutic tool has opened new avenues for clinical use in the allogeneic setting, taking into account that the use of MSC for clinical application is mainly restricted to autologous setting. Hence, establishing clinical-grade hUCBMSC banks is promising given the advantage of immediate availability of umbilical cord tissues for MSC-based therapy production, particularly in already established public cord blood bank facilities. If allogeneic use of MSC proves to be effective and safe, clinical grade hUCBMSC banks may provide unlimited access to cell therapies for regenerative therapy¹⁶.

 

Table 1: Immunophenotyping of cells derived from various sources by flow cytometry

Surface marker	hBMMSC	hUCBMSC	hADMSC
CD14	1.4±0.8	1.3±0.6	2.0±1.1
CD29	97.5±1.9	94.4±7.9	68.5±17.9
CD31	1.8±1.4	1.0±0.9	0.6±0.5
CD34	2.3±1.6	6.1±8.4	1.8±1.1
CD44	100±0.0	96.5±6.0	99.8±0.3
CD45	1.7± 1.5	0.5±0.4	0.9±0.4
CD73	99.1±0.9	93.7±6.3	90.9±3.0
CD90	83.1±20.3	66.4±11.2	62.5±16.9
CD105	90.3±12.1	68.2±27.2	75.0±14.1
CD106	4.3±1.6	6.3±7.5	2.0±1.2

 

 

Table 2: Immunophenotyping of cells derived from various sources by flow cytometry

Source	Cell type	Capability	Bone Regeneration
Adipose	hADMSC	Osteogenic+++	+++
Bone Marrow	hBMMSC	Osteogenic+++	+++
Umbilical Cord Blood	hUCBMSC	Osteogenic+ / Chondrogenic+	+

 

Fig. 1: RT-PCR analysis for tri-lineage differentiation-associated markers in MSCs derived from bone marrow (hBMMSCs), umbilical cord blood (hCBMSCs), and adipose tissue (hADMSCs). The expression of osteogenic (DLX5 and RUNX2)²¹.

 

POTENTIAL OF BONE REGENERATION:

Bone defect regeneration remains problematic in the fields of medicine and dentistry. Various efforts have been made to accelerate bone regeneration, one of them being Mesenchymal Stem Cells (MSCs) therapy which offers a promising solution for deep approach bone regeneration. The MSCs possess multipotent capabilities, paracrine and autocrine, and migration capacity to the tissue and directly initiate healing and regeneration¹⁷. Bone is a highly specialized organ that serves many purposes. First and foremost, bone plays a structural role, but it serves other functions such as mineral storage (calcium, sodium, phosphate, and magnesium) and hematopoiesis as it stores marrow. Bone’s structural role includes protection for the brain, spinal cord, and chest organs, as well as rigid internal support for the limbs. The internal architecture of bone accounts for its lightness and high tensile strength, which is a result from its hollow and tubular shape composed of a collagen matrix with mineral deposits¹⁸.

 

In numerous pre-clinical experiments, MSCs have been transplanted into animal models for generating mesodermal derivatives such as bone, muscle, cartilage via differentiation in order to repair the damaged tissues. The self-renewal ability of MSCs along with their differentiation potential contributes to tissue homeostasis. Some of the multifunctional characteristics of MSCs that make them ideal for therapeutic use are their ability to home into the site of tissue injury, ability of engraftment, and immunosuppressive function as exerted by immunocytes. The beneficial effects of MSCs on bone remodeling are mainly provided by a paracrine effect. The secretome of the hADMSCs contains various endocrine factors involved in bone activity. In bone regeneration, implanted hADMSCs secrete various osteoblast-activating factors, such as macrophage colony-stimulating factor (MCSF), receptor activator of nuclear factor kappa-B ligand (RANKL), BMP-2, BMP-4, and hepatocyte growth factor (HGF), and bone-related extracellular matrix proteins, including HGF and extracellular matrix proteins, corroborating their paracrine role in osteogenesis¹⁸.

 

hUCBMSC have advantages over hBMSCs in terms of lower immunogenicity, faster proliferation rate, extensive availability, and no ethical concerns, making hUCBMSCs a promising cell source for bone tissue engineering. There is some evidence that hUCBMSCs possess therapeutic potential for bone tissue engineering to treat bone fractures and defects. To reinforce their osteogenic induction, hUCBMSCs are often combined with a scaffold¹⁹. There are several advantages of using hUCBMSCs among various mesenchymal stem cells. First, hUCBMSCs are less immuonogenic and can avoid host immune surveillance because they do not require a close human leukocyte antigen (HLA) match owing to the naive nature of a newborn's immature system. Because of this reason, hUCBMSCs can be used regardless of gender, allergy, and blood grouping. Second, they show a high expanding capacity compared with bone marrow-derived mesenchymal stem cells (BMMSCs). Third, hUCBMSCs are ‘off-the-shelf’ products and can be used whenever it is wanted and as much as it is needed²⁰. Compared with bone marrow MSCs, hUCBMSCs possess the multiple differentiation potential of adult stem cells and have become an ideal seed cell. Isolated cell culture of hUCBMSCs is relatively easy to perform, and cells with uniform cell phenotypes can be obtained without in vitro enzymes or other substances for digestion and purification, and hUCBMSC isolation is non-invasive and is not associated with ethical issues regarding sourcing¹¹.

 

DISCUSSION:

Local bone loss that may arise from trauma, tumor, infection, periprosthetic osteolysis or congenital musculoskeletal disorders constitutes a major worldwide socioeconomic problem frequently requiring surgical intervention. Although bone autografts are the gold standard for filling the defect, the available amount of autologous bone is limited, and its harvesting is associated with several drawbacks like the additional donor-site morbidity²². Bone reconstruction is a complex physiological process exhibiting encapsulation. The interaction between external environment parameters and validating the predictive power of the model by internal factors makes a dynamic balance between the osteoclast experimental training and testing data and osteoblasts that affect bone formation²³. Tissue engineering is a discipline that aims to restore the structure and function of damaged tissues. Cells, scaffolds, and factors have been used in combination to create constructs capable of facilitating tissue regeneration. Tissue engineering of bone and cartilage has progressed from simple to sophisticated materials with defined porosity, surface features, and the ability to deliver biological factors²⁴. Biological, molecular, and clinical evidence support the potential use of MSCs as an alternative therapy in diverse pathologies²⁵.

 

Bone formation in vivo is a sequential multistep process comprising activation, chemotaxis, mitosis, and differentiation of cells and is regulated by many interacting factors. Therefore, combinations of growth factors are more efficient for tissue regeneration applications than the use of single ones²². Regeneration of bone injuries has been the target for stem cell-based therapies over the past decade in those conditions associated with major bone defects, loss of bone substance, or delayed fracture union. Although MSC application shows relative clinical success in improving osteonecrosis, mandibular and bony defects or fracture remodeling, full recovery of the bone structure and function remains a challenge for tissue engineering approaches on the bone¹⁶.

 

MSCs are involved in growth, wound healing, and replacement of cells that are lost daily by exfoliation or in pathological conditions. Different studies show that they induce repair in neuronal, hepatic, and skeletal muscle after infusion in both preclinical and clinical models. These qualities make them a potential tool for tissue engineering and tissue repair^7,25,26. hUCBMSC is a promising candidate for cell therapy due to their potent multilineage differentiation, enhanced self-renewal capacity, and immediate availability for clinical use. Clinical experience has demonstrated satisfactory biosafety profiles and the feasibility of hUCBMSC application in allogeneic setting. However, the use of hUCBMSC for bone regeneration has not been fully established¹⁶. hUCBMSCs may be a better source of therapeutic cells compared with hBMMSCs due to their ease of procurement, consistent proliferation and growth characteristics, and consistent therapeutic properties²⁷.

 

hBMSCs have been most extensively studied both in pre-clinical and clinical experiments: the effects of BMSCs in fracture healing, spinal fusion, and osteonecrosis have been sufficiently demonstrated. hADMSCs possess osteogenesis capacity, but their efficacy and safety still need to be proven in further research⁵. hADMSCs has come to the forefront in many studies focused on bone healing using stem cell regenerative therapies. hADMSCs has demonstrated bone regenerative capabilities³. Table. 1 shows that the cells were negative for CD14, CD31, CD34, CD45 and CD106, which are known markers of hematopoietic and endothelial cells, whereas the MSCs were positive for CD29, CD44, CD73, CD90 and CD105, which are known markers of MSCs²¹. Osteogenesis-related gene runt-related transcription factor 2 (RUNX2), distal-less homeobox 5 (DLX5), which plays a key role in the development of skeletal elements and the commitment of MSCs to the osteoblast lineage was only expressed in the hBMMSC and hADMSC.  RUNX2 expression in the hBMMSC was lower than in the other cell types. These results again support our theory that hBMMSC and hADMSC possess tri-lineage differentiation potential²⁸. In contrast, the DLX5-expressing hUCBMSC developed an osteogenic phenotype, albeit at varying degrees and this coincided with DLX5 expression. The levels of DLX5 expression do not necessarily correlate with osteogenic potential. The discrepancy in DLX5 expression and the osteogenic potential of hADMSC may be explained by the differences in the expression of growth factors, growth factor receptors and transcription factors involved in osteogenesis. DLX5, one of the key transcription factors for osteoblast differentiation, is a predictive marker for the osteogenic potential of MSCs (Figure.1)²¹. Table. 2 shows the capability of hADMSC and hUCBMSC by comparing hBMMSC which shows that osteogenic hADMSC is higher than hUCBMSC and hBMMSC. Therefore, it can be interpreted that the ability of hADMSC bone regeneration is higher than hUCBMSC and hBMMSC^{21,29,30,31,32,33}.

 

CONCLUSION:

The ability of hADMSC bone regeneration is higher than hUCBMSC due to the higher osteogenesis capacity of hADMSC compared with hUCBMSC which leads to bone and cartilage formation.         

 

ACKNOWLEDGEMENT:                       

This research has been discussed and supported by Doctoral Degree Study Program in Military Dentistry Science at Faculty of Dentistry, Padjadjaran University, Bandung, Indonesia. We would like thanks to the team of Faculty of Dentistry, Padjadjaran University, Bandung, Indonesia.

 

CONFLICT OF INTEREST:

There are no conflicts of interest

 

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Received on 11.04.2020            Modified on 14.06.2020

Accepted on 10.07.2020         © RJPT All right reserved