Osteogenesis in Healthy and Senescent Mesenchymal Stem Cells: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Heri Suroto.

Mesenchymal stem cells (MSCs) are stem cells with the potential ability to differentiate into various cells and the ability to self-renew and resemble fibroblasts. These cells can adhere to plastic to facilitate the culture process. MSCs can be used in research into tissue biotechnology and rejuvenation medicine. MSCs are also beneficial in recipient tissue and differentiate as a breakthrough strategy through paracrine activity.

  • cellular senescence
  • mesenchymal stem cells
  • MSCs senescence
  • osteogenesis

1. Introduction

Senescence is a time-dependent functional decline that affects most organisms and is an important risk factor for human diseases such as malignancy, glucose metabolism disorder, cardiovascular disease, and neurodegenerative process [1]. Cellular senescence can be defined as persistent cell cycle termination associated with stereotyped phenotypic changes [2,3,4][2][3][4]. The cellular senescence process can be altered in response to external stimuli, including the lessening of telomere length, oxidative stress, deoxyribonucleic acid (DNA) injury, and oncogene activation [5].
Mesenchymal stem cells (MSCs) are known as multiple, mature, non-hematopoietic stem cells collected separately from bone marrow [6]. MSCs have been harvested and extracted from different tissues and organs, such as peripheral blood, umbilical cord, bone marrow, Wharton’s Jelly, placental tissue, breast milk, and other growth contributing organs, via different methods [7,8,9][7][8][9].
Inside a normal bone, an osteogenesis process is regulated by biological stages involving MSCs, leading to the modeling and partial remodeling process, causing proliferation [13][10]. Other processes also occur, such as lineage differentiation, expression of specific markers, extracellular matrix (ECM) mineralization, and collagen expression. In aging bone, other known culprits than bone resorption activity are MSC impairment, shifting of osteogenesis to adipogenesis, and decreased capacity for renewal activity [14,15][11][12]. This imbalance activity may increase the risk of fractures [16][13]. Transcription factors in normal conditions are needed in MSC differentiation to maintain normal osteogenesis in a well-fashioned mechanism. The sequential activation of Runx2 and Osterix transcriptions is the master regulator of osteogenesis. At the same time, CCAAT enhancer-binding protein beta (CEBPβ), gamma (CEBPγ), alfa (CEBPα), and peroxisome proliferator-activated receptor-gamma (PPARγ) are the master regulators of adipogenesis [17,18][14][15]. 

2. Cellular Senescence Process

2.1. Cell Cycle Arrest

The number of stimuli that cause aging gradually increases, and the mechanisms involved are extensively studied. These stimuli are signaled through various signaling pathways, many of which activate p53 (encoded with TP53 in humans and Trp53 in mice), all of which are essentially cyclin-dependent kinase (CDK) inhibitors. Agents are p16 (also known as INK4A; encoded by CDKN2A), p15 (also known as INK4B; encoded by CDKN2B), p21 (also known as WAF1; encoded by CDKN1A) and p27 (encoded by CDKN1B). Inhibition of the CDK-cyclin complex leads to growth arrest. A critical factor in implementing aging is the hypo-phosphorylated RB (retinoblastoma family) [32][16]. This accumulation leads to sustained RB family protein activity, inhibition of E2F transactivation, and cell cycle arrest. It is irreversible when proteins of the RB or p53 family are later inactivated [33][17]. These efforts are supported by the heterogeneity of E2F target genes [34][18], the action of cytokines secreted by senescent cells [35][19], and the increased production of long-lived ROS [36][20].

2.2. Decreased Telomere Length and Response to DNA Injury

Telomeres function like a molecular clock that records the replication history. In particular, “erosion” of telomeres due to sequential cell division that cannot preserve telomere length can lead to reduced telomere length and “replicative senescence” type. The loss of telomeres is recognized as DNA damage. It thus triggers a DNA damage response (DDR) similar to ionizing radiation and chemotherapy drugs. Telomeres are also highly susceptible to external DNA damage [37,38][21][22]. This is partly due to the inaccessibility of telomeres to DNA damage repair machinery, from yeast to humans [39][23]. Key mediators of DDR are the DNA damage kinases related to phosphorylation such as ATM, ATR, CHK1, and CHK2. The activation of several cell cycle proteins, including phosphorylation p53, activates the expression of p21, which binds and inhibits several CDK-cyclin complexes, particularly those involving CDK2 [5].

2.3. CDKN2A Locus Depression

Duplications are also associated with the CDKN2A locus (also known as INK4A and ARF), which encodes two important tumor suppressor factors, p16 and ARF. ARF regulates the stability of p53 by inactivating the p53-degrading protein MDM2 ubiquitin ligase E3 [40,41][24][25]. The CDKN2A locus is usually expressed at insufficient levels in new tissues but is repressed with age [42][26]. Although the molecular mechanisms responsible for inhibition of CDKN2A are not fully understood, it is well known that they are highly dependent on loss of the Polycomb inhibitor complex [43,44,45][27][28][29]. It should be clear that DNA damage can lead to degradation by reducing the level of ARF protein [46][30].

2.4. Stress-Inducing Senescence and ROS

ROS levels rise after various types of stress, including chemotherapy drugs, loss of telomere defenses, DNA damage, and oncogene activation [39,43][23][27]. A role for aging-related oxidative stress is evidenced by antioxidant treatment delaying or preventing aging [47,48,49][31][32][33]. Mechanistically high levels of intracellular ROS induced by the RAS-RAF-MEK-ERK cascade activate p38 MAPK to increase p53. transcriptional activation and p21 activation [40][24].

2.5. Aging Related Oncogene

Normal cells respond to the activation of many oncogenes by cellular senescence. Oncogene-induced by senescence was first detected in the oncogenic form of ASD in human fibroblasts. The list of oncogenes that can cause aging has grown to about 50. Aging caused by oncogenes occurs in vivo and is well known to act as a brake in the early stages of carcinogenesis. Inhibition of the CDKN2A locus is a common hallmark of oncogenic aging [41,42][25][26].
In addition, this type of senescence may also strongly induce DDR due to DNA damage caused by abnormal DNA replication [50,51][34][35] and ROS [5,39,40,41,42,43][5][23][24][25][26][27]. The relative importance of these mechanisms (p16, ARF, or p53 induced by DDR) is cell type dependent. In mice, the ARFp53 pathway is an important activator of oncogene-induced senescence [52][36], whereas in humans the DDRp53 pathway appears to play a more important role than the ARFp53 pathway [53][37]. Finally, p16 plays a small role in stimulating senescence in mice but is essential in human cells [54][38].

2.6. Senescence-Associated Secretory Phenotype (SASP)

Senescent cells produce a complex pro-inflammatory response known as the SASP and IL-8. Chemokines (monocyte chemoattractant protein (MCP) and macrophage inflammatory protein (MIP)), growth factors (transforming growth factor (TGF-β) and granulocyte-macrophage colony-stimulating factor (GMCSF)), proteases [55,56,57,58,59][39][40][41][42][43] and secretome aging messages (SMS) [60,61][44][45] are also included.
Secretion of these and similar proteins by senescent cells induces inflammation and, at least in some cases, may be necessary for phagocytotic senescent cell clearance [62,63][46][47]. SASP components, especially TGF-β, can also induce senescence of adjacent cells in a paracrine manner through mechanisms that generate ROS and DNA damage [64][48].

3. Mesenchymal Stem Cells (MSCs)

MSCs, also known as stromal cells, are a collection of tissue-specific progenitor cells that can renew in long-term and potential differentiation as an important role in tissues and organs balance [65,66,67,68,69,70][49][50][51][52][53][54]. These cells coexist and overlap due to plasticity differentiation and support of the functioning tissue. This depends on the source of the tissue, donor characteristics, culture media, and administration methods, “stem” or “stromal” [67][51]. MSCs, in this term, become a long reservoir for the next generation of somatic cells and other supernumerary cells.
MSCs can be isolated in large clusters from many sources such as tissues in bone marrow, perinatal, and adipose, and can be expanded by ex vivo means. The adhesion ability to plastic can be defined with a set of phenotype markers such as CD73+, CD90+, CD105+, CD11b- or CD14-, CD19- or CD79a-, CD34-, CD45-, and HLA-DR-. The definition is also not limited to the capacity of differentiation towards chondrocytes, adipocytes, and osteoblasts [71][55].
Senescence in organisms is correlated with a decrease of MSC activity which implies the declining of stem cell functions. This slowing activity reduces tissue repair and maintenance speed, a characteristic of senescence. As an example, fractures in osteoporotic bone associated with advanced age are more prone to delay in healing because of diminished function and amount of MSCs [72][56].
MSCs may be an optimizing option in the regenerative medicine aspect and tissue repair, with immunomodulatory benefit because of a convenient method of isolation and replication [73,74,75][57][58][59]. Paracrine activity in MSCs via soluble factor, exosome and micro-vesicles may also help ease tissue modulation in the microenvironment, inhibiting inflammation and contributing to the repair process [66,76,77][50][60][61].
MSCs secrete many soluble factors that work as autocrine or paracrine, including chemokines, proteases, extracellular matrix (ECM) growth factors, and cytokines, possibly used as cell-free-based therapy sources. Multiple functions such as pro-proliferative activity, anti-inflammation, pro-angiogenic, anti-apoptotic, and anti-fibrotic functions are due to the interaction between cells and secretion of abundant soluble factors. Anti-inflammatory secretome activity releases prostaglandin E2, Transforming growth factor- β (TGF-β), IL-6, IL-1, Tumor necrosis factor- inducible gene six protein (TSG6), IL-1 receptor antagonist (IL-1RA), and nitric oxide [78][62].

4. Osteogenesis in Healthy and Senescent MSCs

Aging in tissue and organ stages is related with stem cells. In human and animal research, aging impacts MSCs via a decreased series of MSCs within the bone marrow, and bias differentiation into adipocytes, which sacrifice osteoblasts. MSCs, or stromal mesenchymal cells, can grow in culture plate, proliferate in vitro, and differentiate into osteoblasts, chondrocytes and adipocyte. In addition, MSCs have been isolated from fats, pulp, amniotic fluid, placenta, and Wharton’s jelly [108][63].
Skeletal tissue MSCs are composed of bone and cartilage in response to growth factors such as bone morphogenetic proteins (BMPs) and Wnt molecules. MSCs express the bone morphogenetic transcription factors Runx2 and Osterix (Osx), which differentiate into osteoblasts. MSCs can express Sox9 and differentiate into cartilage, thereby forming chondrocytes. MSCs can also express CCAAT/enhancer-binding protein (C/EBPa) and peroxisome proliferator-activated receptor (PPAR-γ), which differentiate into bone marrow adipocytes [109,110][64][65].
In addition to osteoblasts, bone additionally incorporates osteoclasts that act as bone resorption elements from the HSC monocytic lineage. HSCs are pluripotent stem cells within the bone marrow that may produce all forms of blood cells. HSC-derived monocytes can grow to become macrophages and granulocytes, similar to osteoclasts. Osteoclasts are giant cells with many nuclei that secrete proteases which wreck bone matrix proteins and collagen. In addition, osteoclasts act synergistically with osteoblasts via complicated binding mechanisms. For example, MSC and osteoblasts secrete MCSF, RANKL, and OPG to modify osteoclast formation, and monocyte and osteoclasts secrete numerous boom elements to alter osteoblast formation. Osteoblast-mediated osteogenesis and osteoclast-mediated bone resorption are reservoirs of equilibrium. Osteogenesis outweighs bone resorption during a boom, and bone mass increases [111,112][66][67]. Senile osteoporosis is ordinarily because of a lower quantity of MSCs within the bone marrow and a lower osteogenesis, due to the differentiation of distorted MSCs into adipocytes at the price of osteoblasts [89][68]. MSC is known to have an osteogenesis and adipogenesis differentiation capability which is altered in older MSCs. Older MSCs tend to differentiate into adipocytes, thus the markers of osteogenesis, such as alkaline phosphatase (ALP) activity and osteocalcin (OC) expression, were down-regulated in aged MSCs during culture in the bone-forming media [113][69].
Aging can directly affect osteogenesis by preventing proliferation and inhibiting the function of MSCs, which can differentiate into a wide variety of cell populations, including osteoblasts and adipocytes [14,33,114][11][17][70]. Induction of aging is primarily regulated by the p53 and retinoblastoma pathways (pRb/p16INK4a) [115,116][71][72]. Expression of p16INK4a and the presence of lesions due to unresolved DNA damage are the best markers of aging in vivo [42,117,118][26][73][74]. Both pathways are closely associated with bone homeostasis. For example, pRb is directly involved in the differentiation of bone progenitor cells because it can bind to and activate major osteogenesis regulators such as Runx2 [119,120][75][76]. pRb can also suppress adipogenic differentiation through a mechanism of action on the peroxisome proliferator-activated receptor-γ subunit (PPAR-γ) [121][77]. Decreased p53 or p21CIP1 regulators may increase the likelihood of mouse stromal cell proliferation and osteogenesis differentiation [118,121,122][74][77][78]. Increased expression of the osteogenesis transcription factors Runx2 and Osterix (Osx) may be the underlying mechanism of control of osteogenesis by p53.
Several studies have shown that the osteogenesis activity of MSCs deteriorates with increasing lifespan, which is associated with decreased osteogenesis efficiency. This osteogenesis is associated with the expression of RUNX2/CBFA1 via the PI3KAKT signaling pathway. It is an important transcription factor of the osteogenesis/chondrogenic lineage as an activator and marker of MSC osteogenesis [123,124][79][80]. A slight decrease in its expression has been observed with age [125][81]. The core factor-kB ligand-receptor activator (RANKL), which is essential for osteoclast differentiation and maintenance, has been highly expressed in late MSC. Transforming growth factor (TGF/SMAD3) signaling pathways are essential for osteogenesis differentiation and may induce ERK phosphorylation. ERK inhibitors have been shown to suppress TGFβ-induced osteogenesis differentiation [126,127][82][83].
Potentiation of adipogenic MSCs’ capacity is relative and may be worsened or enhanced. The general view is that the adipogenesis activity of MSCs may decrease in conjunction with usual culture media. PPARµ is a member of the ligand-activated nuclear receptor superfamily, and may act as adipogenic-specific transcription factor, including transcriptional activation. This PPARµ targets different genes related to lipid metabolism and adipocyte development. The expression may be decrease, alongside with senescence, and the impairment of this expression along with C/EBP may alter the fate of MSCs’ osteoblast lineage. The inhibition pathway of C/EBP and PPARµ is mediated via WNT/β-catenin signaling and is therefore aimed at MSC differentiation into osteoblasts. Hence, it can become the key regulator of adipogenesis and osteogenesis [54][38]. Phosphorylation of AKT by insulin may suppress the expression of Forkhead box O3 (FOXO3) and activate PPAR, which opposes the balance of differentiation and enhances adipogenesis activity.
FOXOs play an essential role in bone turnover and osteoclast activation by decreasing the ROS substance [59][43]. FOXO1, 3, and 4 deletions in the osteoclast progenitor increase osteoclast proliferation and formation, thus reducing the trabecular and cortical bone mass. On the contrary, the increased function of FOXO3 in turn inhibits the osteoclast differentiation and increases the survival of osteoblast via catalase and superoxide dismutase. The last two enzymes mentioned prevent oxidative injury occurrence [47,60][31][44]. FOXO1 also helps collect glutathione, which decreases ROS via the sulfhydryl moieties redox-active pathway [128][84].
The PI3K-PKB/AKT regulates the transcriptional activity of the FOXOs via the canonical pathway. FOXOs and Sirt1 are related to the increase in bone lifespan through the balance of bone formation and resorption, while IGF1 and IGF-R1 act oppositely. Sirt1 modifies posttranslational FOXOs and prevents bone turnover while enhancing bone formation. Wnt signaling and insulin-like signaling (ILS) are reduced with FOXOs activity. The decreased signaling of Wnt may induce protein aggregation, which contributes to early cell deterioration [129][85].
The Insulin/Insulin Growth Factor 1 (IGF-1) signaling system (IIS) regulates metabolism, including activity concerning an organism’s nutrition balance, growth, and development. Mammals have three sepae ligand molecules of insulin /IGF-1 receptors: insulin, IGF-1, and IGF-2. There are also three diverse insulin/IGF tyrosine kinase receptors: insulin receptor (IR), IGF-1 receptor (IGF-1R), and the so-called orphan IR related receptor (IRR). The activated IGF-1 or insulin receptors begin with phosphorylation in intracellular substrates, then dock for intracellular effectors. The site of this docking process for intercellular effectors includes growth-factor-receptor-bound protein-2 (Grb2) and the p85 regulatory subunit of PI-3K. Activation of Ras-MAPK and PI-3K-PKB/AKT pathway occurs as 2 major signals. The last pathway mentioned has been known to regulate insulin/IGF-1 signaling metabolic effect [130][86].
Sirtuin1 (Sirt1)3 is an NAD+-dependent deacetylase that delays and opposes aging-related processes in lower organisms in mammals [131,132][87][88]. Sirt1 is responsible for biological activity such as DNA repair, metabolism of energy, mitochondrial homeostasis, and tumor suppression. This activity is linked with the deacetylation of the FOXO family and β-catenin, which acts as co-activator of canonical Wnt signaling [133][89].

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