Cell Tissue Bank DOI 10.1007/s10561-013-9403-z

REVIEW PAPER

The effect of non-growth factors on chondrogenic differentiation of mesenchymal stem cells Xiujie Zhang · Yumin Zhang · Zhiqiang Wang · Qijia Li · Baoxing Li

Received: 29 June 2013 / Accepted: 9 October 2013 © Springer Science+Business Media Dordrecht 2013

Abstract Chondrogenic differentiation of mesenchymal stem cells (MSCs) in vitro usually requires the presence of growth factors in the culture condition. But many cost-effect methods can successfully fulfill this without addition of these cytokines. This article focuses upon the effect of non-growth factors on the chondrogenic differentiation of MSCs and the concise introduction of the potential mechanism of these methods. Keywords Non-growth factors · Chondrogenesis · Mesenchymal stem cells

Introduction Articular cartilage is an avascular, hypocellular tissue that has a limited capacity for self-repair. Regeneration

Y. Zhang · B. Li (&) China Institute for Radiation Protection, Shanxi Provincial Tissue Bank, Taiyuan 030006, China e-mail: [email protected] X. Zhang Southern Medical University, Guangzhou, China Z. Wang Affiliated Hospital of Hebei United University, Tangshan, China Q. Li Hebei United University, Tangshan, China

of articular hyaline cartilage is a major clinical challenge for orthopedist and researcher (Hunziker 2002). Most recent studies have focused on the development of new techniques, such as implantation of articular chondrocytes (ACs) and tissue-engineered constructs to improve cartilage restoration. As we know, the lack of autologous chondrocytes and complications which arise when harvesting them is attempted have made mesenchymal stem cells (MSCs) a superior candidate for cartilage regeneration due to their chondrogenic potential. As MSCs also possess osteogenic ability, it is important to induce the chondrogenic state of MSCs for the construction of chondral engineering. This is especially true when they were implanted in vivo. Mesenchymal stem cells (MSCs) are widely distributed in a variety of adult tissues and usually harvested from bone marrow or adipose tissue. Although subsequent expansion is not complicated, effective as well as optimal chondrogenesis requires the presence of growth factors where even two kinds of cytokines are often adopted (Freyria and Mallein-Gerin 2012; Shintani et al. 2013; Rui et al. 2010; Patil et al. 2012). However, the expensive cost and potential disadvantages of these cytokines, such as safety or side effect, are still worth considering. Therefore, to look for a costeffect and optimized method without using of growth factors for MSCs chondrogenesis is promising. In recent years, many researchers have worked to seek the best way to solve this challenge. Table 1 summarizes the major findings of researches that used non-growth

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Equine BMSCs

Bovine BMSCs

Human BMSCs

Human BMSCs

Kisiday et al. (2009)

Mouw et al. (2007)

Li et al. (2009a)

Scha¨tti et al. (2011)

Human ADSCs

Human BMSCs

Pelaez et al. (2009)

Chen et al. (2013)

Rabbit BMSC

Huang et al. (2004)

Rabbit MSCs

Human BMSCs

Miyanishi et al. (2006)

Cui et al. (2007)

Rabbit BMSCs

Jeong et al. (2012)

Rabbit BMSC

Human BMSCs

Singh et al. (2013)

Lee et al. (2006)

Rabbit BMSCs

Zheng et al. (2010)

Pig BMSCs

Rabbit BMSCs

Zhang et al. (2012)

Human ADSCs

Human ADSCs

Wu et al. (2010)

Liu et al. (2010a, b)

Pig BMSCs

Xue et al. (2012)

Lv et al. (2012)

Cell

Study

SPEMF and PEMF

LIUS

LIUS

Porcine chondrocytes

Pig chondrocytes

Compression plus shear

Oscillation and

Dynamic compression

Dynamic compression

Cyclic compression

Cyclic compression

IHP

Chondrocyte and IHP

Cellulose and silk

CH, CAH

Collagen I hydrogel

HA

ACSs

Induction medium

Table 1 Effect of non-growth factors on chondrogenic differentiation

2D-HA and 3D-pelle

Cells-PGA scaffold

3-D alginate culture

3D co-culture

3D co-culture and subcutaneous

3D scaffold, amplitude (0.4 mm, ±25°),1.0 Hz for 1 h/day for 15 days

3D scaffold, 10 %strain, 1.0 dynamic compression

Cell-agarose constructs, 10 % strain, 1.0 Hz for 1, 3, 20 h

Cell-agarose constructs, 10 % strain, 0.3 Hz, 4.5 or 12 h/day

Fibrin gel scaffolds, 10 %strain, 0.1, 0.5,1.0 Hz for 4 h/day for 3 days and type II collagen

Cell-agarose constructs, 10 % strain, 1.0 Hz for 4 h/day for 3 days

10 MPa, 1 Hz for 4 h/day

3D co-culture and IHP(0−0.2 MPa, 2 h/ day for 7 days)

2D membranes-cells

Hydrogel-BMSCs composite

Cell aggregates in hydrogel

Cell aggregation

BMSC-ACS constructs

Induction conditions

t Enhanced the expression of SOX-9, collagen type II, and aggrecan

Formed hyaline cartilage-like tissue, expressed Sox9, aggrecan and TIM-2

Increased matrix formation and expressed Col 2, aggrecan and Sox-9

Formed cartilage-like tissues, type II collagen and glycosaminoglycan

Formed cartilage-like tissue implantation

Upregulated Col 2, AGG, COMP, and Sox9

Expressed Col 2, AGG Hz for 1 h/day for 7 days

Upregulated collagen II, lowest sGAG expression, downregulated aggrecan

Increased proteoglycan synthesis

Upregulated aggrecan

Expressed type II collagen gene

Increased SOX9, type collagen II, and aggrecan mRNA levels

Higher magnitudes of IHP promoted chondrogenesis of co-cultured MSCs

Upregulated SOX9, aggrecan, and type II collagen

Showed the characteristic of chondrocytes and secreted cartilage ECM

Formed neo-cartilage tissue with ECM deposition

Expressed Sox9, type II collagen and aggrecan

Expressed aggrecan, COMP, type II collagen and Sox9

Main findings

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ECM extracellular matrix, BMSCs bone marrow-derived mesenchymal stem cells, ACSs acellular cartilage sheets, COMP Cartilage Oligomeric Matrix Protein, ADSCs adiposederived stromal cells, HA hyaluronan, CH collagen-hydrogel, CAH collagen-alginate-hydrogel, IHP intermittent hydrostatic pressure, sGAG sulfated glycosaminoglycan, Col 2 collagens type II, AGG aggrecan, LIUS low-intensity ultrasound, CDDO-Im/CDDO-EA 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-Imidazolide/Ethyl amide

Induced expression of SOX9, collagen IIa1, and aggrecan Monolayer culture Human BMSCs Suh et al. (2012)

CDDO-Im and CDDO-EA

Expressed Sox9, collagen II and AGG 2D discs-cells Human MSCs Glennon-Alty et al. (2013)

Polyacrylate substrates and Mouse MSCs、KSCs

Cell Study

Table 1 continued

Induction medium

Induction conditions

Main findings

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factors. However, little consonance can be realized among them. Performances of different strategies, such as mechanical and physical stimulation, are still a matter of debate due to the different parameters. The purposes of this review are to: (1) highlight the feasible method of inducing MSCs chondrogenesis without the addition of growth factors. (2) Provide rational choice for chondrogenesis of MSC before initiating in vivo animal and clinical studies.

Scaffolds and ECM Scaffolds play a vital role in the tissue regeneration process. There are many scaffold types have been used for cartilage engineering (Zhou et al. 2006; Liu et al. 2010a, b; Yang et al. 2008; No¨th et al. 2007; Ahtiainen et al. 2012; Izal et al. 2013). Scaffolds that can stimulate chondrogenic differentiation of stem cell without growth factor supplementation provide promising and cost-effective methods for regenerative medicine. Acellular cartilage sheets (ACSs), which greatly maintain natural tissue components, structure and growth factors excreted by chondrocyte, have been successfully used for cartilage engineering. After decellularization, some authors detect growth factors remained in ACSs by ELISA (Xue et al. 2012). The amounts of growth factors in the decellularized group were similar to those in unprocessed sheets. However, the chondrogenic differentiation was only confirmed by RT-PCR analysis in vitro culture. In vivo, results indicated that ACSs possess a chondrogenic induction activity, but were not strong enough to induce bone marrow-derived mesenchymal stem cells (BMSCs) to form even cartilage. So, the activities of these growth factors in ACSs and decellularization techniques that are able to preserve functional proteins remain controversy. To date, many studies have confirmed that extracellular matrix molecules can regulate intracellular signaling and differentiation of MSC. The theory of direct activation of signal transduction by matrix molecules through integrin receptors has been well established. Cell–ECM interactions mainly depend on integrin cell-surface receptors. Cellular functions such as proliferation, migration, survival and differentiation are regulated by these receptors (Geiger and Yamada 2011; Geiger et al. 2001). For example, a hyaluronan (HA)-enriched microenvironment can

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initiate and enhance chondrogenesis of human adipose derived stem cells (hADSCs) (Wu et al. 2010), the major mechanism is mainly due to the interaction of HA and CD44 (HA-CD44), a cell-surface receptor of HA (Wu et al. 2013). Matrix stiffness also plays an important role in MSC differentiation. A soft matrix that mimics the stiffness of brain tissue promotes neurogenic differentiation, whereas stiffer matrix induces myogenic or osteogenic properties (Engler et al. 2006). However, an in vitro study indicated that a soft matrix like collagen hydrogel have inherent inductivity for the chondrogenic differentiation of bone marrow mesenchymal stem cell (Zhang et al. 2012), this may result from the local high cell density and close cell–cell interaction created by the contraction of collagen hydrogel. Several studies also support this theory (Tang et al. 2010; Johnstone et al. 1998). In another in vivo study (Zheng et al. 2010), the author encapsulated bone marrow mesenchymal cells in collagen-based hydrogel and then enclosed the compound in diffusion-chambers which allow the body fluid to permeate and preclude the host cells to invade. After being subcutaneously implanted in the back of a rabbit, the cell-like chondrocytes were homogenously spread and the extracellular matrix of cartilage was secreted, indicating the chondrogenic differentiation of BMSCs. These studies showed that certain matrices such as collagen and collagen-base hydrogels could build a cellular microenvironment mimicking chondrogenic environment to induce chondrogenesis of MSCs. In one study, authors fabricated a compound of cellulose and silk in a 75:25 ratio. They hypothesized that an optimum combination of matrix stiffness and elasticity and appropriate combination of hydroxyl and amino functional groups may enhance the chondrogenic differentiation of stem cells (Singh et al. 2013). The chondrogenic marker genes SOX9, aggrecan, and type II collagen were significantly upregulated by seeding human bone mesenchymal stem cells on this blending without the addition of specific growth factors. Their results suggest that the optimum physical and chemical properties of the material and suitable interaction between MSCs and scaffold may influence the differentiation fate of MSCs. Altogether the composition and stiffness of the scaffold and ECM contribute to the determination of stem cell fate. But when, where and how the scaffold and ECM influences the stem cell’s fate

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remains to be investigated (Singh and Schwarzbauer 2012).

Mechanics stimulation Mechanical stimulations are very important for the functional maintenance of articular cartilage. Deformational and hydrostatic pressures, for example, can affect the metabolic activities of chondrocytes and their biosynthesis via mechanotransduction (Elder and Athanasiou 2009; Hung et al. 2004). Therefore, many studies focus on the role of mechanical stimulation as a chondrogenic factor in the cartilage tissue engineering field and enumerate a number of bioreactors. However, as kinesics of articulating joints are complicated and it is difficult to carry out such research in vivo. Thus, there is no bioreactor which can completely simulate the intra-articular environment. Hydrostatic pressure (HP) Cartilage is a highly hydrated tissue and water is trapped within the solid matrix. When the joint undergo loading, the stresses between the fluid and solid phases of the tissue will be translated to HP due to fluid phase pressurization (Elder and Athanasiou 2009). Intermittent HP in the physiological range seems to promote matrix synthesis, but constant pressure seems impertinent (Elder and Athanasiou 2009). Some researchers make use of 3D co-culturing of MSCs and chondrocyte and intermittent HP to control chondrogenesis of MSCs without biochemical agents (Jeong et al. 2012). According to their results, the higher the stimulation magnitudes of intermittent HP (≥0.10 MPa), the more effective proliferation and differentiation of co-cultured MSCs. Other authors have reported that chondrogenesis can be successfully induced by co-culture of adipose-driven stromal cells and chondrocytes (Lv et al. 2012). In their work, however, they firstly examined the synergic, combined effect of 3D co-culture and mechanical stimuli. Hydrostatic pressure (HP) has been shown to regulate the chondrogenic differentiation of mesenchymal stem cells. Cell–matrix interactions also play a vital role in the chondrogenic differentiation of MSCs (Steward et al. 2011). A recent study confirmed that hydrostatic pressure could enhance

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chondrogenesis of BMSCs in a biomaterial-substratedependent manner (Steward et al. 2012). Therefore, the choice of matrix for cartilage engineering will be a considerable factor. Although the fact of HP can contribute to the chondrogenic differentiation and expression of chondrogenic mRNA levels (Miyanishi et al. 2006) have been known, little consensus has been reached regarding the ideal conditions such as HP parameters (magnitude, frequency, amplitude, loading time), particularly when different culture environments and matrices are used. Moreover, it is seemed that the evidence of construct neo-cartilage by sole application of HP is insufficient.

chondrogenesis of mesenchymal stem cells (MSCs) suspending in agarose in the presence of TGF-β3. The synthetic effects of dynamic compression and growth factor in the chondrogenic genes expression and matrix synthesis are complicated. Dynamic compression can up/down-regulate aggrecan gene expression in the absence/presence of TGF-β and enhance matrix distribution and the mechanical properties of MSC-seeded constructs with sustained TGF-β exposure (Campbell et al. 2006; Huang et al. 2010). Therefore, a more complex interplay must exist between the biophysical and biochemical environment in regulating chondrogenesis of MSCs.

Compression

Synergistic effects of compression and shear

During normal daily movements, the major weight bearing joints such as hip and knee will bear average loadings of approximately 0.5–7.7 MPa and average compression amplitudes of more than 13 % have been confirmed (Afoke et al. 1987; Mow and Wang 1999; Von Eisenhart et al. 1999). An unconfined cyclic compression has the capacity to elicit the chondrogenic differentiation of rabbit BMSC in agarose culture without the need for exogenous growth factor supplementation (Huang et al. 2004). However, agarose is not a biodegradable matrix under normal physiological environments. Instead some authors make use of fibrin gel for supporting the cyclic compression-induced chondrogenesis of mesenchymal stem cells (Pelaez et al. 2009). Their results suggest that appropriately modulated cyclic compression (10 % strain) can maintain cell viability within scaffolds and elicit an up regulation in chondrogenic genes similar to that observed in agarose construct studies. Some authors (Kisiday et al. 2009) indicated that in the absence of the chondrogenic cytokine transforming growth factor beta (TGF-β), dynamic compression applied for 12 h per day led to significantly greater proteoglycan synthesis than in unloaded TGF-β-free cultures, although at a rate that was approximately 20–35 % of unloaded TGF-β cultures. Similarly, other studies have observed little dynamic compression-induced stimulation of gene expression or matrix synthesis in the absence of chondrogenic growth factors (Mouw et al. 2007). However, other researchers (Thorpe et al. 2008) argue that dynamic compressive loading can inhibit

As the construction of joint is very complicated and articular motion is a combination of compressive, tensile and shear deformations, alone application of mechanics stimulation are insufficient to mimic the in vivo conditions. Shear stress is a potent modulator of the amount and type of extracellular matrix synthesis (Gemmiti and Guldberg 2009). Combining the application of compression and shear provide a microenvironment similar to the in vivo joint environment. Compared to uniaxial loading, multiaxial loading have been manifested its advantage in terms of chondrogenic gene expression and differentiation (Grad et al. 2006; Li et al. 2009a, b). Besides, dynamic combined compression–shear stimulation could increase both collagen and proteoglycan synthesis (Waldman et al. 2007). In order to determine the synergistic effect of the combination of cyclic axial compression with surface shear on chondrogenic differentiation of human bone marrow-derived stem cells, some researchers applied compression, shear or a combination of both stimuli onto fibrin/polyurethane composites in which human mesenchymal stem cells were embedded without exogenous growth factors were added to the culture medium (Scha¨tti et al. 2011). Their results indicated that both application of compression or shear alone was insufficient for the chondrogenic induction. However, the combination of shear superimposed upon dynamic compression led to significant increases in chondrogenic gene expression. Decidedly, including the application of compression and shear provides another intriguing method for chondrogenic differentiation.

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Co-culture with chondrocyte As stem cells may be affected by the vicinal cells and matrix, the co-culturing systems were extensively adopted (Bian et al. 2011; Tortelli and Cancedda 2009). A few recent studies adopt MSCs co-culture with chondrocyte to induce chondrogenesis. BMSCs and adipose derived stem cells (ADSCs) could differentiate into chondrocytes with the presence of chondrocytes (Liu et al. 2010a, b; Lv et al. 2012). Although the mechanism has not been completely clarified, the possible interpretation is chondrocytes may secrete some growth factors that could induce the differentiation of MSCs, such as IGF-1 and TGFβ1. Furthermore, a chondrogenesis microenvironment supply by the chondrocytes and cell-to-cell communication may play vital role in the chondrogenesis of MSCs (Lv et al. 2012). However, some authors argue that the increased cartilage production in pellet co-cultures of chondrocytes and BMSCs is due to a trophic role of the MSC in stimulating chondrocyte proliferation and matrix production rather than MSCs actively undergoing chondrogenic differentiation (Wu et al. 2012). It is therefore certain that the details of MSCs chondrogenesis in coculturing systems would require further investigation.

Other physical and chemistry factors Low-intensity ultrasound (LIUS), a physical stimulus, has gained increasing attention to use for cartilage engineering due to its simple and cost-effective application. It could not only activate chondrocyte phenotypes but also improve cartilage repair (Parvizi et al. 1999; Nishikori et al. 2002; Zhang et al. 2002; Min et al. 2006, 2007; Choi et al. 2006; Cook et al. 2001; Nieminen et al. 2004). Moreover, it has been shown to be a promising intervention to enhance the chondrogenic differentiation of MSCs even without the presence of growth factors (Lee et al. 2006; Hangody et al. 2001). Instead of forming fibrocartilage, LIUS preconditioning of rabbit MSCs in PGA scaffold in vitro without TGF significantly enhanced the chondrogenic differentiation and formation of hyaline cartilage-like tissues when implanted in vivo (Cui et al. 2007). This may be explained by the mechanotrans-

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duction pathways mediated by integrins (Zhou et al. 2004). However, the possibility that LIUS treatment induced the expression of TGF-β family proteins should not be completely excluded (Lee et al. 2006). Electromagnetic field (EMFs) stimulation, another physical stimulus, has been used for the treatment of bone fractures, especially in nonunions (Bassett et al. 1974; Griffin et al. 2008; Heckman et al. 1981). Some authors confirmed that pulse electromagnetic field (PEMF) stimulation is effective in promoting the osteogenic differentiation of BMSCs (Jansen et al. 2010). However, in an appropriate chondrogenic microenvironment, single-pulse electromagnetic field (SPEMF) and (PEMF) can also be used as a tool for enhancing chondrogenic differentiation in the absence of any protein or chemical induction factors (Chen et al. 2013). Besides physical stimuli, the effect of surface chemistry on the chondrogenic potential of different mesenchymal cell has been investigated. Polyacrylate substrates modelled on the functional group composition and distribution of the Arg-Gly-Asp (RGD) integrin-binding site could induce MSCs to undergo chondrogenesis in the absence of exogenous TGF-β (Glennon-Alty et al. 2013). As the fact of MSCs could express their own TGF-β and high concentrations in the supernatant of MSCs cultured in vitro have been confirmed (Rossignol et al. 2009; Liu et al. 2012). Moreover, TGF-βs secreted from the MSCs are able to bind to polyacrylate substrates and create a high local concentration that is sufficient to induce signalling. So, it is possible that TGF-β supplementation is not indispensable to induce MSCs chondrogenesis on the polyacrylate substrates. Recently, there was a report of the use of drugs for the induction of chondrogenesis. Synthetic oleanane triterpenoids (SO) have been known to induce differentiation in many different cell types (Suh et al. 1999). Some authors firstly evaluated induce chondrogenic activity of new SO (CDDO-Ethyl amide and CDDO- midazolide) (Suh et al. 2012). Because SO can upregulate the activity of TGF-β and BMPs (Suh et al. 2003) and these cytokines and their signaling proteins (Smads) are known to play important roles in chondrogenesis (Song et al. 2009). Thus, the rationale for the potential use of SO as chondrogenic agents is well-founded.

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Discussion As reviewed here, there are many methods which were originally being used for induce MSCs chondrogenesis without the presence of growth factors. Although some basic principles of these strategies are not totally clear. It is absolutely true that chondrogenesis of MSCs can be successfully induced, to one degree or another, by these non-growth factors. The future holds many exciting challenges within the field of complex MSCs chondrogenesis. New technologies and methods will contribute to provide some of the solutions. This article aims to provide more cost-effect and reasonable choice for chondrogenesis of MSC before initiating in vivo animal and clinical studies. Although the preferred method still remains a concern to some researchers, with close collaboration among researchers, the encouraging future will come true soon.

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