滑膜间充质干细胞修复软骨损伤：具有临床转化机制的话题

doi:10.3969/j.issn.2095-4344.2014.02.024

中国组织工程研究 ›› 2014, Vol. 18 ›› Issue (2): 307-313.doi: 10.3969/j.issn.2095-4344.2014.02.024

• 组织构建综述 tissue construction review • 上一篇下一篇

滑膜间充质干细胞修复软骨损伤：具有临床转化机制的话题

陈康，曾意荣，樊粤光，曾建春，李杰，李飞龙，范帅

广州中医药大学第一附属医院三骨科，广东省广州市 510405

收稿日期:2013-10-23 出版日期:2014-01-08 发布日期:2014-01-08
通讯作者: 曾意荣，博士，教授，硕士生导师，主任医师，广州中医药大学第一附属医院三骨科，广东省广州市 510405
作者简介:陈康，男，1987年生，广东省汕头市人，医师，主要从事软骨损伤疾病的研究。
基金资助:
国家自然科学基金项目(81273784)，广东省自然科学基金项目(1015104070100 0045) ，高等学校博士学科点专项科研基金项目(20104425110011)

Synovial mesenchymal stem cells-based therapy for cartilage repair
An issue concerning clinical transformation

Chen Kang, Zeng Yi-rong, Fan Yue-guang, Zeng Jian-chun, Li Jie, Li Fei-long, Fan Shuai

Third Department of Orthopaedics, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China

Received:2013-10-23 Online:2014-01-08 Published:2014-01-08
Supported by:
the National Natural Science Foundation of China, No. 81273784; the Natural Science Foundation of Guangdong Province, No. 10151040701000045; Research Fund for the Doctoral Program of Higher Education of China, No. 20104425110011

摘要/Abstract

摘要：

背景：软骨损伤目前仍然是临床上难以完全治愈的一大难题。近来，滑膜间充质干细胞的发现为该病变的治疗带来了新的希望。
目的：综合近几年文献探讨滑膜间充质干细胞的特性、培养条件、临床前及临床研究等关于软骨修复的研究进展。
方法：应用计算机检索1993年1月至2013年5月PubMed数据库和SpringerLink数据库中的相关文章，检索词为“synovial mesenchymal stem cells, cartilage repair”，并参阅其他相关的著作及高影响因子的相关文献.
结果与结论：最终纳入符合标准的文献37篇。滑膜间充质干细胞较之其他间充质干细胞具有更强的增殖、集落形成和软骨化能力。骨关节炎、类风湿关节炎等疾病可影响其细胞特性。已有大量文献集中于其体外细胞培养及动物体内细胞移植方面的研究。然而，该治疗方法的研究尚处于初步阶段。关于其细胞鉴别特性、理想培养条件及高质量临床研究方面的报道仍相当缺乏。总而言之，尽管研究有待深化，滑膜间充质干细胞仍不失为一种未来修复软骨损伤领域有前景的细胞资源。

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

全文链接：

关键词: 组织构建, 软骨组织工程, 滑膜间充质干细胞, 软骨损伤, 软骨修复, 细胞移植, 细胞治疗, 国家自然科学基金

Abstract:

BACKGROUND: Cartilage injury is still one of the clinical problems difficult to be treated completely so far. Recently, the discovery of synovial mesenchymal stem cells (SMSCs) has brought about the new hope to cartilage repair.
OBJECTIVE: To explore the process concerning SMSCs-based therapy for cartilage repair in the past few years, such as the characteristics of SMSCs, culture conditions, preclinical and clinical studies, and then to summarize the literatures published in recent years.
METHODS: A computed-based online search of PubMed and SpringerLink databases was performed using the key words of “synovial mesenchymal stem cells, cartilage repair” for literatures published from January 1993 to May 2013.
RESULTS AND CONCLUSION: Finally, 37 articles were included. SMSCs have a greater proliferative capability, colony-forming potential and chondrogenic potential than other mesenchymal stem cells. The diseases such as osteoarthritis and rheumatoid arthritis can influence the characteristics of SMSCs. Numerous articles have aimed at the studies of cell culture in vitro and cell transplantation in vivo. However, the process of SMSCs therapy is mostly at its preliminary stage. Reports on its unique characteristics, optimal culture conditions and the high-quality clinical studies are still largely lacking. In a word, though further studies are needed, SMSCs appear to be a promising cell source for cartilage repair in the future.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

全文链接：

Key words: mesenchymal stem cells, synovial membrane, cartilage, tissue therapy

中图分类号:

R318

陈康，曾意荣，樊粤光，曾建春，李杰，李飞龙，范帅. 滑膜间充质干细胞修复软骨损伤：具有临床转化机制的话题[J]. 中国组织工程研究, 2014, 18(2): 307-313.

Chen Kang, Zeng Yi-rong, Fan Yue-guang, Zeng Jian-chun, Li Jie, Li Fei-long, Fan Shuai. Synovial mesenchymal stem cells-based therapy for cartilage repair
An issue concerning clinical transformation[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(2): 307-313.

图/表（结果） 1

Differentiated properties of SMSCs compared with other MSCs

SMSCs have a greater proliferative capability and colony-forming potential than other stem cell sources in vitro, including bone marrow, periosteum, muscle and fat. In the early years, analysis by De Bari and colleagues^[2] had already shown the superior proliferative abilities of SMSCs, which maintained growth rates over 30 population doublings, and demonstrated multilineage differentiation capacities. Recently, Yoshimura et al^[3] compared the proliferation of rat mesenchymal stem cells derived from the bone marrow, synovium, periosteum, adipose tissue and muscle: implanted with the same amount of cells at passage 1, the SMSCs showed the greatest proliferative rate among them, with the largest amount of cloning and the cells per clone. Jo et al^[4]demonstrated the colony-forming potential per nucleated cell in SMSCs to be 1 in 12.5-80 in comparison with 1 in 10³-10⁴ in BMSCs. Sakaguchi et al^[5] reported that plating at optimal density for 14 days came out with an average of 21 000 cells per 1 mg of synovium. They also found that SMSCs retained the proliferative capacity over four passages, whereas muscle MSCs and adipose MSCs lost their proliferative capacity over four and seven passages. Nimura et al^[6] compared the proliferation of human SMSCs and human BMSCs with autologous human serum. They found that human SMSCs expressed higher levels of platelet-derived growth factor (PDGF) receptor α, than did human BMSCs. Neutralizing PDGF, which was contained highly in human serum, decreased the proliferation of human SMSCs.

Although SMSCs are distinct from other MSCs, their surface epitope expressions are similar. Particularly, there is very little difference between surface epitopes for SMSCs and those for BMSCs. Several studies have shown that both cells types are positive for CD44, CD73, CD90 and CD105Hermida-Gómez et al^[11] analyzed SMSCs in the membrane of osteoarthritis patients using flow cytometry, and discovered that cells expressed both CD44 and CD105 more than CD44 and CD90, CD 90 and CD105. The cells expressing SMSCs surface marker mainly distribute in the lining layer of synovial membrane, with very few in other region. Interestingly, Arufe et al ^[13]studied the subpopulations of SMSCs enriched for CD73, CD106, and CD271 markers, which had different profiles of cells positive for the MSC markers CD44, CD69, CD73, CD90, and CD105., but negative for CD14, CD34, and CD45. Among them, only CD90 is found to be significantly higher in mean fluorescent intensity in SMSCs than BMSCs, which may explain the increased chondrogenic potential of SMSCs^[7-8]. SMSCs are also positive for CD9, CD10, CD13, CD54, CD55, CD166, and D7-FIB, but they are not unique to SMSCs^[7]. Subsequently, studies have found that SMSCs can abundantly express CD49d, but BMSCs do not^[9]. It has been reported that SMSCs can retain the surface epitope markers of CD73, CD90 and CD105, after six passages^[10]. Another study reveals that it can retain not only the expression of CD90 (endotheliocyte marker)^[11]but also the expression of D7-FIB (fibroblasts marker)^[12] after the subculture.

Chondrogenesis of SMSCs compared with other MSCs

Multiple studies have demonstrated the greatly chondrogenic capacity of SMSCs among MSCs. As cell-to-cell contact may promote chondrogenesis and inhibit osteogenesis in cells^[14], pellet culture has been used in many studies. Sakaguchi et al^[5]reported that using pellet culture multiple rat MSCs, the pellets larger than 1 mm were shown in SMSCs, BMSCs and periosteum MSCs cultures. In contrast, pellets in muscle and adipose MSCs were both smaller than 1 mm. The pellets from SMSCs and periosteum MSCs were also heavier than those from BMSCs, muscle and adipose MSCs. What’s more, in SMSCs, synthesis of chondroitin sulfate and hyaluronan was highest.

There are more in-vitro studies than in-vivo studies to examine the chondrogenesis of SMSCs. Koga et al ^[15]found that SMSCs, seeded in collagen gel, showed an enhanced chondrogenic capacity in rabbit osteochondral defects compared with other MSCs. Significant cartilage matrix and well histological score were found in defects with SMSCs and BMSCs. In contrast, defect repaired with adipose and muscle MSCs were badly healed^[5].

There are several problems worth considering in the application of SMSCs, importantly, such as dedifferentiation, degeneration and ossification of hyaline cartilage. Recent studies have showed that the capacity of undergoing osteogenesis in SMSCs seems to be reduced compared with that in other MSCs. SMSCs have been reported by Koga et al^[16]to retain metachromatic staining at least for 24 weeks in repaired cartilage and do not show signs of ossification. Shirasawa et al^[14]found that, as the culture time of SMSCs increased, endogenous BMPs and BMP receptors were not detected or decreased. Throughout the culture, expression of the osteogenic marker runx-2 did not change. The pellet did not reveal signs of hypertrophy or bone formation, though some osteogenic protein was detected. Another important appearance is that only a small amount of bone sialoprotein mRNA was expressed by the pellets in SMSCs, and neither did osteocalcin mRNA nor signs of calcification.

Suitable culture conditions for SMSCs in cartilage repair

Growth and differentiation factors

The most common growth and differentiation factors used in culturing SMSCs recently include transforming growth factor-β (TGF-β) superfamily, basic fibroblast growth factor (bFGF), bone morphogenetic protein 2 (BMP-2). These factors, especially, the synergistic action of TGF-β and BMP-2, have been proved to be able to stimulate the chondrogenesis of SMSCs. Fan and colleagues engineered cartilage using SMSCs in vitro with injectable gellan gum hydrogels. The cells were divided into three groups, culturing in TGF-β1, TGF-β3 and BMP-2, respectively. After 42 days, the two TGF-β groups showed more significant chondrogenesis compared with the BMP-2 group^[17]. Subsequently, Rui et al^[18] used BMP-2 to promote the TGF-β3-induced chondrogenesis of SMSCs isolated from human osteoarthritic synovium in a pellet culture system. Compared with the TGF-β3-alone group, cell pellets treated with TGF-β3 and BMP-2 showed a significantly better result in diameter, weight, glycosaminoglycans (GAGs), the level of collagen type II and other chondrogenic markers, except COL10A1^[18]. Recently, Shintani et al ^[19] introduced 10 ng/mL TGF-ß1 into the BMP-2-induced bovine synovial explants that were furnished with SMSCs for the cartilage repair, compared with the same density of FGF-2. The FGF-2 group only increased metachromatic staining for GAGs during the first week of culturing alone, while the TGF-β1 group not only more greatly increased the metachromasia, but also enhanced the biochemically-assayed accumulation of GAGs, when it was presented throughout the entire culturing period. Moreover, at the same time, TGF-β1 arrested the downstream differentiation of cells at an early stage of hypertrophy. Kim et al ^[20] also applied various concentrations of bFGF to monolayer cultures of SMSCs. As a result, SMSCs showed augmented sizes, weights, and GAG accumulation of pellets by bFGF supplementation. Up-regulated messenger RNA and protein expression of type II and type X collagens were also detected. The 10 ng/mL of bFGF was elected as the optimal concentration. Meanwhile, cell shrinkage and increased actin expression were noted.

It is worthwhile to take notice that the TGF-β pathway to induce the chondrogenesis of SMSCs has been reported already. In 2012, Xu et al ^[21] described RhoA/Rho kinase signaling as the regulation of TGF-β1-induced chondrogenesis and actin organization of SMSCs, interacting with the Smad pathway. Primary isolated SMSCs were treated with TGF-β1. C3 transferase, Y27632 and SB431542 were used to evaluate the function of RhoA/Rho kinase and Smads as the specific biochemical inhibitors. As a result, the activation of the RhoA/Rho kinase pathway was in response to the stimulation of TGF-β1 in SMSCs, and concomitantly cytoskeletal reorganization was induced, which was specifically blocked by C3 transferase and Y27632. In addition, the phosphorylation of Smad2/3 was reduced by Y27632 treatment, in a concentration-dependent manner. This may be an important discovery for the successful utilization of SMSCs to achieve articular cartilage tissue engineering.

Other influential factors

Numerous studies about the valuable factors that could regulate the chondrogenesis and proliferation of SMSCs have been reported in the past few years, many of which showed new train of thought to the culturing. Shimaya et al ^[22] added magnesium into the SMSCs-based culturing integrin, and performed assays for adherence and chondrogenesis of SMSCs in vitro and in vivo in a rabbit osteochondral defect model: through the study, the adhesion of human SMSCs to collagen was increased by magnesium, meanwhile inhibited by neutralizing antibodies for integrin α3 and β1. And it promoted synthesis of cartilage matrix during in vitro chondrogenesis of SMSCs, which was diminished by neutralizing antibodies for integrin β1 but not for integrin α3. Positive effects were also found in adherence of human SMSCs to osteochondral defects ex vivo, adherence and cartilage formation of SMSCs in vivo in rabbits^[22]. Another research reported by Shimomura and co-workers^[23] in 2010 focused on the influence of skeletal maturity. They compared the repair quality of damaged articular cartilage between immature and mature pigs, which was explanted by a scaffold-free three-dimensional tissue-engineered construct derived from SMSCs. No skeletal maturity-dependent difference was found in proliferation or chondrogenic differentiation capacity of the porcine SMSCs, suggesting the feasibility of allogenic SMSC-based cartilage repair over generations. Shintani et al ^[24]investigated the effects of dexamethasone upon the TGF-β1- and BMP-2-induced chondrogenesis of different MSCs and microenvironments: in aggregates of SMSCs, DEX exerted remarkable effect on neither TGF-β1 nor BMP-2-induced chondrogenesis. In synovial explants, it inhibited BMP-2-induced chondrogenesis

greatly, but had little impact on the TGF-β1-induced response, showing the fact that steroids are not always necessary for the chondrogenesis of MSCs in vitro. In 2012, Bertram et al ^[25]spanned a range of osmolarities (264-375 mOsm) in the SMSCs-culture media to see the chondrogenic changes of SMSCs isolated from the synovial fluid of normal people or osteoarthritis and rheumatoid arthritis patients. Consequently, SMSCs from arthritic joints showed decreased chondrogenic potential compared to SMSCs isolated from normal synovial fluid. Under the osmolarity conditions for which they were initially derived within, the SMSCs retained increased chondrogenic potential.

Interestingly, the way to culture SMSCs can also influence the property of SMSCs. In 2012, Suzuki et al ^[26]compared the aggregate-cultured SMSCs and the monolayer- cultured SMSCs both isolated from human and rabbits. In in-vitro studies, the human SMSCs derived from aggregates showed higher amounts of cartilage matrix synthesis in pellets than that cultured in a monolayer. In in-vivo studies in rabbits, aggregates of SMSCs could adhere rapidly on the osteochondral defects by surface tension, and furthermore, stay without any loss.

Culture serum

The most common serum used in the SMSCs culturing in recent years contains the autologous human serum, fetal bovine serum (FBS). Nimura et al ^[6]cultured synovial and bone marrow MSCs obtained from 18 donors with autologous human serum or FBS. Notably, human SMSCs expanded more in human serum than in FBS through PDGF, whereas the opposite results were obtained with BMSCs. It also showed that neutralizing PDGF, which receptor is higher in SMSCs than BMSCs, decreased the proliferation of SMSCs with autologous human serum. Later, their group expanded human SMSCs with either autologous human serum or FBS after heat-inactivation. It is demonstrated that heat-inactivated autologous human serum enhanced proliferation of SMSCs. Moreover, heat-inactivation of each types of serum did not affect calcification of SMSCs. And the adipogenesis of SMSCs with autologous human serum was similar to or less than that with FBS^[27].

Scaffolds

The culture scaffold selection is also becoming the study heat point in these years. In 2010, Fan et al ^[17] encapsulated passage-4 monolayer-amplified rabbit SMSCs in injectable gellan gum hydrogels as the culture scaffold followed by culture within TGF-β1, TGF-β3 or BMP-2 for 42 days. The viability of SMSC in hydrogels in these three groups remained high at culture time, demonstrating the potential application in clinical cartilage repair. The researchers also applied the non-degradable poly(ethylene glycol) diacrylate-based hydrogel and biodegradable phosphoester-poly(ethylene glycol)-based hydrogel as three-dimensional scaffolds encapsulated with rabbit SMSCs, and compared the viability of SMSCs in both hydrogels. It is reported that SMSCs continue to have a high viability, and positive SMSC chondrogenesis is successfully achieved in both gels by induction of TGF-β1 or TGF-β3, with the best outcome in the poly(ethylene glycol) diacrylate system^[28]. In 2011, Qi et al ^[29] seeded CD105-positive rat SMSCs onto the chitosan-alginate composite three-dimensional porous scaffolds, which was put into chondrogenic culture medium within TGF-β3 and BMP-2 in vitro. After 2 weeks, cells attached and proliferated well on scaffolds, and secreted extracellular matrix. The sorted cells cultured in scaffolds demonstrated more chondrogenic differentiation as well, compared with non-sorted cells. In 2013, Zhang et al^[30] applied type I collagen scaffold with stromal cell-derived factor-1 to create a matrix environment for SMSCs-based cartilage repair. Through ex vivo and in vitro studies, subchondral bone or type I collagen scaffold was more permissive for SMSCs adhesion than cartilage or type II collagen scaffold.

SMSCs in treatment of other cartilage diseases

Through the literatures available so far, it is certain that diseases around the cartilage can influence the characteristics of SMSCs. Sekiya et al^[31] isolated SMSCs from knee joints of normal people, anterior cruciate ligament injury, mild osteoarthritis and severe osteoarthritis patients, to analyze the relationship between MSCs number in the synovial fluid and the different kinds of knee joint. Through arthroscopy, the MSCs in the synovial fluid were hardly observed in normal volunteers, but the number increased as the grading of osteoarthritis goes up. Jones et al ^[32]evaluated the frequency and multipotency of SMSCs from rheumatoid arthritis patients in relation to synovial inflammation measured using the arthroscopic visual analogue score. It came out with the fact that the chondrogenesis of SMSCs was inhibited in direct relation to visual analogue score and reduced compared with control SMSCs from osteoarthritis patients. They concluded a negative relationship between SMSCs chondrogenic and clonogenic capacities and the joint inflammation in rheumatoid arthritis. Morito-100 ng/mL interleukin-1β, the resultant size of pellets from normal ovine SMSCs has been significantly inhibited. et al ^[33] obtained human synovial fluid from anterior cruciate ligament injury patients around the time of reconstruction surgery and from healthy volunteers, then cultured and examined the MSCs in the synovial fluid. Through the study, the number of MSCs in the synovial fluid from intra-articular ligament injury patients was demonstrated to be 100 times more than those from healthy volunteers. No significant differences in surface epitope and differentiation potential were observed among the cells around the time of the surgery. Ando et al ^[34] isolated SMSCs from six sheep at 2 weeks after experimental anterior cruciate ligament core surgeries: The size of SMSC pellets from operated knees after culturing was significantly smaller than that from contralateral knees. With the addition of 1

Studies in vivo for cartilage repair

Articular cartilage repair with SMSCs has been reported

with an increasing number of animal studies in vivo in these few years, though clinical studies are still largely lacking. Currently it can help to repair cartilage defects to a limited extent in vivo. Koga et al ^[16]created full-thickness osteochondral defects in the knees of adult rabbits, which were filled with labeled SMSCs and covered with periosteum. It was demonstrated that SMSCs were able to form a cartilage matrix with an abundance of sulfated GAGs and type II collagen, and regionally specified in accordance to local microenvironment. Up to 24 weeks, integration with native tissue was noted, while the thickness of the repair tissue decreased. Nimura et al^[6] reported a study using SMSCs transplanted into full-thickness cartilage defects of the knees in rabbits, with a comparison between the autologous serum cultured group and the FBS group. The effect revealed that chondrogenic potential of rabbit SMSCs in vivo was similar in both two groups. Pei et al ^[35] implanted rabbit SMSCs after 1-month incubation into the knees to repair the full-thickness osteochondral defects, along compared with the scaffold group (fibrin glue-saturated PGA) and the empty group (untreated). Six months after implantation, cartilage defects were full of smooth hyaline-like cartilage with no detectable macrophages and type I collagen but a high expression of GAG and type II collagen, which were integrated with the surrounding native cartilage as well, compared with the scaffold and empty groups respectively resurfaced with fibrous-like and fibrocartilage tissue. Zhang et al ^[30] implanted rabbit SMSCs encapsulated in type I collagen scaffold with cell-derived factor-1 into the rabbit to repair partial-thickness defects. Good results were shown that in situ self-repair of partial-thickness defects enhanced 6 weeks post-injury. It also brought out the conclusion that in partial-thickness defects, the inferior self-repair capacity is partially owing to the non-permissive microenvironment. Ando et al ^[36] implanted the in vitro generated scaffold-free tissue-engineered construct derived from porcine SMSCs into the cartilage defects in the medial femoral condyle of 4-month-old pigs. After 6 months, the tissue-engineered construct repaired tissue showed mechanical properties similar to the normal porcine cartilage, as well as secure biological integration to the native cartilage. Nakamura et al^[37]injected porcine SMSCs into the knees with artificial cartilage defects in pigs, compared with the non-treated control knees. Quantification analyses for arthroscopy, histology and MRI all revealed a better outcome in the SMSC-treated knees than in the non-treated control knees.

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[33] Morito T, Muneta T, Hara K, et al. Synovial fluid-derived mesenchymal stem cells increase after intra-articular ligament injury in humans. Rheumatology (Oxford). 2008;47(8):1137-1143.

[34] Ando W, Heard BJ, Chung M, et al. Ovine synovial membrane-derived mesenchymal progenitor cells retain the phenotype of the original tissue that was exposed to in-vivo inflammation: evidence for a suppressed chondrogenic differentiation potential of the cells. Inflamm Res. 2012; 61(6):599-608.

[35] Pei M, He F, Boyce BM, et al. Repair of full-thickness femoral condyle cartilage defects using allogeneic synovial cell-engineered tissue constructs. Osteoarthritis Cartilage. 2009;17(6):714-722.

[36] Ando W, Tateishi K, Hart DA, et al. Cartilage repair using an in vitro generated scaffold-free tissue-engineered construct derived from porcine synovial mesenchymal stem cells. Biomaterials. 2007;28(36):5462-5470.

[37] Nakamura T, Sekiya I, Muneta T, et al. Arthroscopic, histological and MRI analyses of cartilage repair after a minimally invasive method of transplantation of allogeneic synovial mesenchymal stromal cells into cartilage defects in pigs. Cytotherapy. 2012;14(3):327-338

引言

Millions of people suffer from cartilage lesions every year, particularly osteoarthritis. With the aging society coming, the population of such patients mentioned above is becoming even larger. Unfortunately, cartilage lesions mostly result in poor regeneration filled with fibrous tissue, which is greatly inferior to healthy tissue for the biomechanical properties. It is well-known that the cartilage has low intrinsic regeneration potential that mainly limits the repair of defects, which may be due to the avascular and aneural nature of cartilage tissue^[1]. Several surgical techniques have been developed clinically during the past few decades, such as autologous chondrocyte transplantation, microfracture, marrow-stimulating procedures and debridement reducing the discomfort of the injuries. However, these treated defects cannot regenerate as the native form. Recently, mesenchymal stem cells (MSCs) have been suggested as a source for cell-based therapy for cartilage repair, which can reduce the invasiveness and donor site morbidity made by the previous treatments and may lead to superior regenerative results. For these reasons, the cells become a global research hotspot nowadays for cartilage repair. At present, mesenchymal stem cells have been isolated from the bone marrow, adipose, periosteum, muscle, perichondrium, and synovium. Studies have attempted to produce tissues mimicking the native one with bone marrow-derived mesenchymal stem cells (BMSCs) for its chondrogenic potential early. Disappointingly, these attempts thus far have fallen short. The synovial mesenchymal stem cells (SMSCs), first isolated from the synovial membrane in 2001^[2], have attracted increasing attention. The superior chondrogenic potential, proliferative capability

and colony-forming potential of SMSCs have been confirmed, and thus SMSCs is becoming a new kind of promising seed cells for cartilage tissue engineering.

This paper briefly provides an overview of the researches recently available to describe the process concerning the SMSCs-based therapy for cartilage repair. We will carry out this topic through growth kinetics and chondrogenic capacity compared with other MSCs.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

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The systematic review showed an increasing interest in this biological therapy approach for cartilage repair, by which may offer a better engineered cartilage tissue. SMSCs are better than the other MSCs in the superior chondrogenic capacity, proliferative capability and clonoy-forming potential. If the culture technique perfected in the future, the SMSCs will be used as a kind of common seed cells into the cartilage tissue engineering for the cartilage repair. Compared with total joint arthroplasty, the SMSCs-engineered cartilage repair technique will be undoubtably much more minimally invasive, more biocompatible, and importantly, more far away from periprosthetic joint infection. Then, compared with the matrix-induced autologous chondrocyte implantation, the SMSCs-engineered cartilage repair technique can also be easier to harvest seed cells, faster to culture and produce engineered cartilage tissue which is more close to the native one. As a matter of course, the SMSCs-engineered cartilage repair technique will be a fairly promising way for the future cartilage repair. However, knowledge about this topic is still preliminary, and the cartilage tissue produced by SMSCs now is far from perfect as well. To achieve full regeneration, it is important that several crucial areas should be addressed.

Firstly, there is still no specific surface marker being found to identify MSCs clearly, let alone SMSCs. The International Society for Cellular Therapy has defined markers which MSCs are positive and negative for, but this set surely does not select for cells which are most chondrogenic. Several researches have aimed at the subpopulations of SMSCs enriched for CD73, CD106 and CD271 markers^[13]. What deserves to be mentioned is that some subpopulations appear to be more differentiated from others, and show a stronger chondrogenic potential.

Secondly, the optimal condition for cartilage regeneration has not been confirmed yet, such as the optimal factor or combination of factors, the optimal cell dosages to transplant, the most effective delivery system and the best suited biomaterial for cell containment. Among these, the optimal cell dosage to transplant has the least knowledge. The current literature shows the variety in transplanted cell dosage into the defect, making it difficult for clinical outcome comparison. With the addition of different growth factors and various scaffolds, the SMSCs have been tested to result in the better healing of cartilage defects, but there is still no complete regeneration of cartilage defects. Clarifying the biological pathways, which determine the fate of transplanted SMSCs, will undoubtedly take us one step closer. Inspiringly, the TGF-β pathway has already been discovered and valuable findings which may lead to better regulation of the cell culture have been reported^[21]. That is certainly one of the key steps that may lead to final optimal strategy of cell culture and transplanting.

Lastly, recent studies in vivo are mostly preclinical animal studies, whereas the clinical ones performed in patients are rarely few. Though a large amount of preclinical studies have demonstrated the well-treated results in defect area, clinical data may have a more directly evaluated value for the therapy. What’s more, the clinical studies available now are still low-quality, and reliable clinical data based on randomized, double-blind, controlled, long-term, multicenter studies with systematic follow-up are still rarely lacking. Such data are needed, as it might determine the true value of SMSCs-based therapy for cartilage repair and be helpful for the identification of the best indications for the SMSCs-based therapy.

The process dealing with SMSCs so far supports the application of these cells as a source of promising seed cells for cartilage regeneration, which has become a hotspot on research in the recent years. However, knowledge on this therapy is still preliminary, as shown by the prevalence of preclinical studies and the presence of primitive ones among the clinical studies. Randomized controlled studies are needed. The proper combination of responding cells, optimal inductive factors and scaffolds, the most effective cell dose and the most delivery method will hopefully lead to a suitable regenerative way based on SMSCs, which will not only relieve the pain of millions of people, but also regenerate normal and healthy cartilage.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

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滑膜间充质干细胞修复软骨损伤：具有临床转化机制的话题

Synovial mesenchymal stem cells-based therapy for cartilage repair
An issue concerning clinical transformation

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滑膜间充质干细胞修复软骨损伤：具有临床转化机制的话题

Synovial mesenchymal stem cells-based therapy for cartilage repair An issue concerning clinical transformation

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Synovial mesenchymal stem cells-based therapy for cartilage repair
An issue concerning clinical transformation