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Article(id=1246459844539077117, tenantId=1146029695717560320, journalId=1246415837536497731, issueId=1246459843930903036, articleNumber=null, orderNo=null, doi=10.12307/2025.561, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1718294400000, receivedDateStr=2024-06-14, revisedDate=1731254400000, revisedDateStr=2024-11-11, acceptedDate=1726848000000, acceptedDateStr=2024-09-21, onlineDate=1775108785042, onlineDateStr=2026-04-02, pubDate=1766851200000, pubDateStr=2025-12-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1775108785042, onlineIssueDateStr=2026-04-02, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1775108785042, creator=13701087609, updateTime=1775108785042, updator=13701087609, issue=Issue{id=1246459843930903036, tenantId=1146029695717560320, journalId=1246415837536497731, year='2025', volume='29', issue='36', pageStart='7701', pageEnd='7920', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=1, specialIssue=null, createTime=1775108784853, creator=13701087609, updateTime=1775108852483, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1246460127511991018, tenantId=1146029695717560320, journalId=1246415837536497731, issueId=1246459843930903036, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1246460127511991019, tenantId=1146029695717560320, journalId=1246415837536497731, issueId=1246459843930903036, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=7762, endPage=7768, ext={EN=ArticleExt(id=1246459844824289792, articleId=1246459844539077117, tenantId=1146029695717560320, journalId=1246415837536497731, language=EN, title=Mechanism of erythropoietin/erythropoietin receptor signaling pathway in regulating osteogenic differentiation of periodontal ligament stem cells, columnId=1246459844752986623, journalTitle=Chinese Journal of Tissue Engineering Research, columnName=Research, runingTitle=null, highlight=null, articleAbstract=
BACKGROUND:

Erythropoietin/erythropoietin receptor signaling pathway not only participates in bone marrow hematopoiesis, but also regulates the metabolic response of non-hematopoietic tissues, such as brain, heart, skeletal muscle, and adipose tissue. Simultaneously, it can accelerate the mineralization process of periodontal ligament stem cells and reduce oxidative stress damage. However, the mechanism of action on osteogenic differentiation of periodontal ligament stem cells is still unclear.

OBJECTIVE:

To investigate the effect and action mechanism of erythropoietin/erythropoietin receptor signaling pathway on osteogenic differentiation of periodontal ligament stem cells.

METHODS:

Enzyme digestion method was used to isolate and culture periodontal ligament stem cells from periodontal disease patients and healthy people. The mRNA and protein levels of erythropoietin receptor in two kinds of periodontal ligament stem cells were detected by qRT-PCR and western blot assay. Erythropoietin receptor expression was silenced by small interfering RNA (siRNA) or activated by erythropoietin. qRT-PCR and western blot assay were used to detect the expression of erythropoietin receptor, levels of osteogenic marker genes Runt-related transcription factor 2 (Runx2), osteocalcin, osteopontin, and bone sialoprotein. Alkaline phosphatase staining and alizarin red staining were applied to measure osteogenic differentiation ability of periodontal ligament stem cells. The phosphorylation of signal transducer and activator of transcription 5 (STAT5) was detected by western blot assay.

RESULTS AND CONCLUSION:

(1) The results of qRT-PCR and western blot assay showed that the mRNA and protein levels of erythropoietin receptor in periodontal ligament stem cells in the disease group were significantly lower than those in periodontal ligament stem cells in the healthy group. (2) Alkaline phosphatase staining and alizarin red staining showed that knocking down the erythropoietin receptor can inhibit the osteogenic differentiation ability of periodontal ligament stem cells. qRT-PCR results showed that compared with the control group, knockdown of the erythropoietin receptor group significantly reduced expression levels of Runt-related transcription factor 2, osteocalcin, osteopontin, and bone sialoprotein (P < 0.05). (3) qRT-PCR results showed that after erythropoietin treatment, the expression of erythropoietin receptor in periodontal ligament stem cells recovered. Silencing erythropoietin receptor and then administration of erythropoietin treatment reversed the expression level of erythropoietin receptor. Erythropoietin treatment increased the osteogenic differentiation ability of periodontal ligament stem cells in the disease group and the expression level of the osteogenic marker gene Runt-related transcription factor 2 (P < 0.05). Silencing the expression of STAT5 inhibited this effect of erythropoietin. (4) Western blot assay results showed that with the extension of erythropoietin treatment time, the phosphorylation level of STAT5 increased in periodontal ligament stem cells in the disease group (P < 0.05). The above results indicate that erythropoietin restores the osteogenic differentiation ability of pathological periodontal ligament stem cells by inducing the phosphorylation of STAT5.

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背景：

促红细胞生成素/促红细胞生成素受体信号通路除了参与骨髓造血，也参与调节非造血组织，如脑、心脏、骨骼肌、脂肪组织等的代谢反应。同时，激活此信号通路能加速牙周膜干细胞的生物矿化过程，减轻细胞氧化应激损伤，但促进牙周膜干细胞成骨分化的机制尚不清楚。

目的：

探究促红细胞生成素/促红细胞生成素受体信号通路对牙周膜干细胞成骨分化的影响及作用机制。

方法：

采用酶消化法分离、培养牙周疾病患者及健康人群的牙周膜干细胞，采用qRT-PCR和免疫印迹法检测两种牙周膜干细胞中促红细胞生成素受体的mRNA和蛋白表达水平。使用小干扰RNA沉默促红细胞生成素受体，或使用促红细胞生成素诱导促红细胞生成素受体表达激活，然后采用qRT-PCR、免疫印迹法检测促红细胞生成素受体、成骨标志基因Runt相关转录因子2、骨钙素、骨桥素、骨唾液蛋白的表达水平，采用碱性磷酸酶染色、茜素红染色检测牙周膜干细胞成骨分化能力，采用免疫印迹法检测信号转导及转录激活因子5的磷酸化水平。

结果与结论：

①qRT-PCR和免疫印迹法结果显示，疾病组牙周膜干细胞中促红细胞生成素受体的mRNA和蛋白水平显著低于健康组牙周膜干细胞；②碱性磷酸酶染色以及茜素红染色显示，敲低促红细胞生成素受体能抑制牙周膜干细胞的成骨分化能力；qRT-PCR结果显示，与对照组相比，敲低促红细胞生成素受体组Runt相关转录因子2、骨钙素、骨桥素和骨唾液蛋白的表达水平显著降低（P < 0.05）；③qRT-PCR结果显示，促红细胞生成素处理后，牙周膜干细胞中促红细胞生成素受体表达恢复，沉默促红细胞生成素受体后再给予促红细胞生成素处理，逆转了促红细胞生成素受体的表达水平；促红细胞生成素处理后提高了疾病组牙周膜干细胞的成骨分化能力以及成骨标志基因Runt相关转录因子2的表达水平（P < 0.05），沉默信号转导及转录激活因子5表达后，抑制了促红细胞生成素的这种作用；④免疫印迹结果显示，随着促红细胞生成素处理时间的延长，疾病组牙周膜干细胞中信号转导及转录激活因子5磷酸化水平增加（P < 0.05）。上述结果表明，促红细胞生成素通过诱导信号转导及转录激活因子5的磷酸化，恢复病理性牙周膜干细胞的成骨分化能力。

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作者贡献：

孙峥、赵华负责实验设计、实验实施、论文撰写，孙峥负责细胞培养、指标检测、实验数据分析处理，赵华负责数据和文章的校对。

Sun Zheng, Associate chief physician, Department of Stomatology, Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China

孙峥，女，1973年生，吉林省长春市人，汉族，副主任医师，主要从事口腔颌面外科，牙及牙槽外科方向研究。

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Sun Zheng, Associate chief physician, Department of Stomatology, Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China

孙峥，女，1973年生，吉林省长春市人，汉族，副主任医师，主要从事口腔颌面外科，牙及牙槽外科方向研究。

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Sun Zheng, Associate chief physician, Department of Stomatology, Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China

孙峥，女，1973年生，吉林省长春市人，汉族，副主任医师，主要从事口腔颌面外科，牙及牙槽外科方向研究。

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J Mol Histol. 2024; 55(5): 661-673., articleTitle=Angelica sinensis polysaccharides promote extramedullary stress erythropoiesis via ameliorating splenic glycolysis and EPO/STAT5 signaling-regulated macrophages, refAbstract=null), Reference(id=1246459865837752458, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, doi=null, pmid=null, pmcid=null, year=2021, volume=53, issue=5, pageStart=848, pageEnd=863, url=null, language=null, rfNumber=[40], rfOrder=39, authorNames=SEONG S, KIM JH, KIM K, journalName=Exp Mol Med, refType=null, unstructuredReference=SEONG S, KIM JH, KIM K, et al. Alternative regulatory mechanism for the maintenance of bone homeostasis via STAT5-mediated regulation of the differentiation of BMSCs into adipocytes. Exp Mol Med. 2021; 53(5): 848-863., articleTitle=Alternative regulatory mechanism for the maintenance of bone homeostasis via STAT5-mediated regulation of the differentiation of BMSCs into adipocytes, refAbstract=null), Reference(id=1246459865950998674, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, doi=null, pmid=null, pmcid=null, year=2011, volume=286, issue=8, pageStart=6449, pageEnd=6457, url=null, language=null, rfNumber=[41], rfOrder=40, authorNames=BULUT GB, SULAHIAN R, MA Y, journalName=J Biol Chem, refType=null, unstructuredReference=BULUT GB, SULAHIAN R, MA Y, et al. Ubiquitination regulates the internalization, endolysosomal sorting, and signaling of the erythropoietin receptor. J Biol Chem. 2011; 286(8): 6449-6457., articleTitle=Ubiquitination regulates the internalization, endolysosomal sorting, and signaling of the erythropoietin receptor, refAbstract=null)], funds=[Fund(id=1246459856492843744, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, awardId=201903D321141, language=EN, fundingSource=Shanxi Provincial Key Research & Development Project(201903D321141), fundOrder=null, country=null), Fund(id=1246459856627061479, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, awardId=201903D321141, language=CN, fundingSource=山西省重点研发计划项目(201903D321141), fundOrder=null, country=null), Fund(id=1246459856727724782, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, awardId=null, language=EN, fundingSource=Shanxi Provincial Health Commission Research Project, fundOrder=null, country=null), Fund(id=1246459856811610871, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, awardId=null, language=CN, fundingSource=山西省卫生健康委科研课题项目, fundOrder=null, country=null)], companyList=[AuthorCompany(id=1246459848204898864, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, xref=null, ext=[AuthorCompanyExt(id=1246459848213287473, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, companyId=1246459848204898864, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Stomatology, Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China), AuthorCompanyExt(id=1246459848221676083, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, companyId=1246459848204898864, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=山西医科大学第二医院口腔科，山西省太原市　030000)])], figs=[ArticleFig(id=1246459853410030218, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, language=EN, label=Figure 1, caption=Identification of human periodontal ligament stem cells, figureFileSmall=TbknIk06rMrSeej4UIN28g==, figureFileBig=iMDG7ig+kJL22Gcko8BtYg==, tableContent=null), ArticleFig(id=1246459853502304912, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, language=CN, label=图1, caption=人牙周膜干细胞鉴定

图注：图A-D为流式细胞仪检测细胞表面标志物STRO-1、CD146、CD31、CD45；E为牙周膜干细胞经成骨诱导后碱性磷酸酶染色及茜素红染色；F为牙周膜干细胞经成脂诱导后油红O染色。

, figureFileSmall=TbknIk06rMrSeej4UIN28g==, figureFileBig=iMDG7ig+kJL22Gcko8BtYg==, tableContent=null), ArticleFig(id=1246459853699437209, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, language=EN, label=Figure 2, caption=Expression of erythropoietin receptor (EPOR) in periodontitis tissues and periodontal ligament stem cells, figureFileSmall=FJXt7X94OmihsPz5qj2jcA==, figureFileBig=DLSf/PUsUBBRj2eUi1OhLQ==, tableContent=null), ArticleFig(id=1246459853787517598, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, language=CN, label=图2, caption=牙周炎组织及牙周膜干细胞中促红细胞生成素受体（EPOR）的表达

图注：图A，B为GSE16134和GSE10334数据集中EPOR的表达量；C为qRT-PCR检测牙周膜干细胞中EPOR mRNA水平；D为免疫印迹法检测牙周膜干细胞中EPOR蛋白水平。aP < 0.01。CTRL-PDLSCs：健康组牙周膜干细胞；PD-PDLSCs：疾病组牙周膜干细胞。

, figureFileSmall=FJXt7X94OmihsPz5qj2jcA==, figureFileBig=DLSf/PUsUBBRj2eUi1OhLQ==, tableContent=null), ArticleFig(id=1246459855331021482, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, language=EN, label=Figure 3, caption=Knockdown of erythropoietin receptor (EPOR) inhibits osteogenic differentiation of periodontal ligament stem cells, figureFileSmall=yqFNg3DTAMV+i5tsnHYCHw==, figureFileBig=AjsvfHsy4rIZhcC7PgkiMQ==, tableContent=null), ArticleFig(id=1246459855452656300, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, language=CN, label=图3, caption=敲低促红细胞生成素受体（EPOR）抑制牙周膜干细胞成骨分化

图注：图A为免疫印迹法检测牙周膜干细胞中EPOR蛋白表达水平；B为qRT-PCR检测牙周膜干细胞中EPOR mRNA表达水平；C为碱性磷酸酶染色及茜素红染色检测细胞成骨分化能力；D为qRT-PCR检测Runt相关转录因子2、骨钙素、骨桥素、骨唾液蛋白的表达水平。aP < 0.05，bP < 0.01。

, figureFileSmall=yqFNg3DTAMV+i5tsnHYCHw==, figureFileBig=AjsvfHsy4rIZhcC7PgkiMQ==, tableContent=null), ArticleFig(id=1246459855574291125, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, language=EN, label=Figure 4, caption=Erythropoietin (EPO) induction of erythropoietin receptor (EPOR) expresses and promotes periodontal ligament stem cell differentiation, figureFileSmall=axpNVUTG4djCM7qpzMn8UQ==, figureFileBig=tpvyKVtoG8F9XhwS8hPc+w==, tableContent=null), ArticleFig(id=1246459855691731642, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, language=CN, label=图4, caption=促红细胞生成素（EPO）诱导促红细胞生成素受体（EPOR）表达增加，促进牙周膜干细胞成骨分化

图注：图A，B为qRT-PCR检测细胞EPOR mRNA表达水平；C，D为茜素红染色检测细胞成骨分化能力；E为qRT-PCR检测Runx2 mRNA表达水平。aP < 0.05，bP < 0.01。CTRL-PDLSCs：健康组牙周膜干细胞；PD-PDLSCs：疾病组牙周膜干细胞；Runx2：Runt相关转录因子2。

, figureFileSmall=axpNVUTG4djCM7qpzMn8UQ==, figureFileBig=tpvyKVtoG8F9XhwS8hPc+w==, tableContent=null), ArticleFig(id=1246459855809172159, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, language=EN, label=Figure 5, caption=Erythropoietin (EPO) induces phosphorylation of signal transducer and activator of transcription 5 (STAT5) in periodontal ligament stem cells and promotes osteogenic differentiation, figureFileSmall=gPO7SCsUv17Miip2lkTHVQ==, figureFileBig=MU66xtCu/v5/3ykiQbXFsQ==, tableContent=null), ArticleFig(id=1246459855922418376, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, language=CN, label=图5, caption=促红细胞生成素（EPO）诱导牙周膜干细胞中信号转导及转录激活因子5（STAT5）的磷酸化，促进成骨分化

图注：图A为蛋白质免疫印迹法检测细胞促红细胞生成素受体（EPOR）表达水平；B，C为qRT-PCR检测Runt相关转录因子2及骨钙素的表达水平。aP < 0.05，bP < 0.01。

, figureFileSmall=gPO7SCsUv17Miip2lkTHVQ==, figureFileBig=MU66xtCu/v5/3ykiQbXFsQ==, tableContent=null), ArticleFig(id=1246459856027275982, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, language=EN, label=Table 1, caption=

Primer sequences

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列片段长度（bp）
促红细胞生成素受体F：5′- TTC TGT GCT TCA CCG AGC GGT T -3′98
 R：5′- CGA CAC AGC TTC CAT GGC TCA T -3′ 
Runt相关转录因子2F：5′- CCC AGT ATG AGA GTA GGT GTC C -3′103
 R：5′- GGG TAA GAC TGG TCA TAG GAC C -3′ 
骨钙素F：5′- CGC TAC CTG TAT CAA TGG CTG G -3′91
 R：5′- CTC CTG AAA GCC GAT GTG GTC A -3′ 
骨桥素F：5′- CGA GGT GAT AGT GTG GTT TAT GG -3′84
 R：5′- GCA CCA TTC AAC TCC TCG CTT TC -3′ 
骨唾液蛋白F：5′- GGC AGT AGT GAC TCA TCC GAA G -3′86
 R：5′- GAA AGT GTG GTA TTC TCA GCC TC -3′ 
β-actinF：5′- AGA GCC TCG CCT TTG CCG ATC C -3′106
 R：5′- CTG GGC CTC GTC GCC CAC ATA -3′ 
), ArticleFig(id=1246459856266351316, tenantId=1146029695717560320, journalId=1246415837536497731, articleId=1246459844539077117, language=CN, label=表1, caption=

引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列片段长度（bp）
促红细胞生成素受体F：5′- TTC TGT GCT TCA CCG AGC GGT T -3′98
 R：5′- CGA CAC AGC TTC CAT GGC TCA T -3′ 
Runt相关转录因子2F：5′- CCC AGT ATG AGA GTA GGT GTC C -3′103
 R：5′- GGG TAA GAC TGG TCA TAG GAC C -3′ 
骨钙素F：5′- CGC TAC CTG TAT CAA TGG CTG G -3′91
 R：5′- CTC CTG AAA GCC GAT GTG GTC A -3′ 
骨桥素F：5′- CGA GGT GAT AGT GTG GTT TAT GG -3′84
 R：5′- GCA CCA TTC AAC TCC TCG CTT TC -3′ 
骨唾液蛋白F：5′- GGC AGT AGT GAC TCA TCC GAA G -3′86
 R：5′- GAA AGT GTG GTA TTC TCA GCC TC -3′ 
β-actinF：5′- AGA GCC TCG CCT TTG CCG ATC C -3′106
 R：5′- CTG GGC CTC GTC GCC CAC ATA -3′ 
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促红细胞生成素及受体信号通路调控牙周膜干细胞成骨分化的机制
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孙峥 , 赵华
中国组织工程研究 | 研究原著 2025,29(36): 7762-7768
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中国组织工程研究 | 研究原著 2025, 29(36): 7762-7768
促红细胞生成素及受体信号通路调控牙周膜干细胞成骨分化的机制
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孙峥, 赵华
作者信息
  • 山西医科大学第二医院口腔科，山西省太原市　030000

    • Sun Zheng, Associate chief physician, Department of Stomatology, Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China

    孙峥，女，1973年生，吉林省长春市人，汉族，副主任医师，主要从事口腔颌面外科，牙及牙槽外科方向研究。

Mechanism of erythropoietin/erythropoietin receptor signaling pathway in regulating osteogenic differentiation of periodontal ligament stem cells
Zheng Sun, Hua Zhao
Affiliations
  • Department of Stomatology, Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
出版时间: 2025-12-28 doi: 10.12307/2025.561
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摘要
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背景：

促红细胞生成素/促红细胞生成素受体信号通路除了参与骨髓造血，也参与调节非造血组织，如脑、心脏、骨骼肌、脂肪组织等的代谢反应。同时，激活此信号通路能加速牙周膜干细胞的生物矿化过程，减轻细胞氧化应激损伤，但促进牙周膜干细胞成骨分化的机制尚不清楚。

目的：

探究促红细胞生成素/促红细胞生成素受体信号通路对牙周膜干细胞成骨分化的影响及作用机制。

方法：

采用酶消化法分离、培养牙周疾病患者及健康人群的牙周膜干细胞，采用qRT-PCR和免疫印迹法检测两种牙周膜干细胞中促红细胞生成素受体的mRNA和蛋白表达水平。使用小干扰RNA沉默促红细胞生成素受体，或使用促红细胞生成素诱导促红细胞生成素受体表达激活，然后采用qRT-PCR、免疫印迹法检测促红细胞生成素受体、成骨标志基因Runt相关转录因子2、骨钙素、骨桥素、骨唾液蛋白的表达水平，采用碱性磷酸酶染色、茜素红染色检测牙周膜干细胞成骨分化能力，采用免疫印迹法检测信号转导及转录激活因子5的磷酸化水平。

结果与结论：

①qRT-PCR和免疫印迹法结果显示，疾病组牙周膜干细胞中促红细胞生成素受体的mRNA和蛋白水平显著低于健康组牙周膜干细胞；②碱性磷酸酶染色以及茜素红染色显示，敲低促红细胞生成素受体能抑制牙周膜干细胞的成骨分化能力；qRT-PCR结果显示，与对照组相比，敲低促红细胞生成素受体组Runt相关转录因子2、骨钙素、骨桥素和骨唾液蛋白的表达水平显著降低（P < 0.05）；③qRT-PCR结果显示，促红细胞生成素处理后，牙周膜干细胞中促红细胞生成素受体表达恢复，沉默促红细胞生成素受体后再给予促红细胞生成素处理，逆转了促红细胞生成素受体的表达水平；促红细胞生成素处理后提高了疾病组牙周膜干细胞的成骨分化能力以及成骨标志基因Runt相关转录因子2的表达水平（P < 0.05），沉默信号转导及转录激活因子5表达后，抑制了促红细胞生成素的这种作用；④免疫印迹结果显示，随着促红细胞生成素处理时间的延长，疾病组牙周膜干细胞中信号转导及转录激活因子5磷酸化水平增加（P < 0.05）。上述结果表明，促红细胞生成素通过诱导信号转导及转录激活因子5的磷酸化，恢复病理性牙周膜干细胞的成骨分化能力。

牙周膜干细胞  /  促红细胞生成素  /  促红细胞生成素受体  /  信号转导及转录激活因子5  /  成骨分化  /  牙周炎  /  工程化干细胞
BACKGROUND:

Erythropoietin/erythropoietin receptor signaling pathway not only participates in bone marrow hematopoiesis, but also regulates the metabolic response of non-hematopoietic tissues, such as brain, heart, skeletal muscle, and adipose tissue. Simultaneously, it can accelerate the mineralization process of periodontal ligament stem cells and reduce oxidative stress damage. However, the mechanism of action on osteogenic differentiation of periodontal ligament stem cells is still unclear.

OBJECTIVE:

To investigate the effect and action mechanism of erythropoietin/erythropoietin receptor signaling pathway on osteogenic differentiation of periodontal ligament stem cells.

METHODS:

Enzyme digestion method was used to isolate and culture periodontal ligament stem cells from periodontal disease patients and healthy people. The mRNA and protein levels of erythropoietin receptor in two kinds of periodontal ligament stem cells were detected by qRT-PCR and western blot assay. Erythropoietin receptor expression was silenced by small interfering RNA (siRNA) or activated by erythropoietin. qRT-PCR and western blot assay were used to detect the expression of erythropoietin receptor, levels of osteogenic marker genes Runt-related transcription factor 2 (Runx2), osteocalcin, osteopontin, and bone sialoprotein. Alkaline phosphatase staining and alizarin red staining were applied to measure osteogenic differentiation ability of periodontal ligament stem cells. The phosphorylation of signal transducer and activator of transcription 5 (STAT5) was detected by western blot assay.

RESULTS AND CONCLUSION:

(1) The results of qRT-PCR and western blot assay showed that the mRNA and protein levels of erythropoietin receptor in periodontal ligament stem cells in the disease group were significantly lower than those in periodontal ligament stem cells in the healthy group. (2) Alkaline phosphatase staining and alizarin red staining showed that knocking down the erythropoietin receptor can inhibit the osteogenic differentiation ability of periodontal ligament stem cells. qRT-PCR results showed that compared with the control group, knockdown of the erythropoietin receptor group significantly reduced expression levels of Runt-related transcription factor 2, osteocalcin, osteopontin, and bone sialoprotein (P < 0.05). (3) qRT-PCR results showed that after erythropoietin treatment, the expression of erythropoietin receptor in periodontal ligament stem cells recovered. Silencing erythropoietin receptor and then administration of erythropoietin treatment reversed the expression level of erythropoietin receptor. Erythropoietin treatment increased the osteogenic differentiation ability of periodontal ligament stem cells in the disease group and the expression level of the osteogenic marker gene Runt-related transcription factor 2 (P < 0.05). Silencing the expression of STAT5 inhibited this effect of erythropoietin. (4) Western blot assay results showed that with the extension of erythropoietin treatment time, the phosphorylation level of STAT5 increased in periodontal ligament stem cells in the disease group (P < 0.05). The above results indicate that erythropoietin restores the osteogenic differentiation ability of pathological periodontal ligament stem cells by inducing the phosphorylation of STAT5.

periodontal ligament stem cell  /  erythropoietin  /  erythropoietin receptor  /  signal transducer and activator of transcription 5  /  osteogenic differentiation  /  periodontitis  /  engineered stem cells
孙峥, 赵华. 促红细胞生成素及受体信号通路调控牙周膜干细胞成骨分化的机制. 中国组织工程研究, 2025 , 29 (36) : 7762 -7768 . DOI: 10.12307/2025.561
Zheng Sun, Hua Zhao. Mechanism of erythropoietin/erythropoietin receptor signaling pathway in regulating osteogenic differentiation of periodontal ligament stem cells[J]. Chinese Journal of Tissue Engineering Research, 2025 , 29 (36) : 7762 -7768 . DOI: 10.12307/2025.561
正文
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0　引言　Introduction
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牙周炎是一种常见的牙齿支持组织的感染性疾病，如不及时治疗会导致牙齿松动、脱落，甚至颌骨骨质破坏[1-3]。常用的治疗方法如物理治疗、牙周手术等效果不佳，因此，组织再生以及利用干细胞重建牙周组织和骨组织成为近年来的主要研究方向[4]。牙周膜是一种紧密的纤维结缔组织，连接牙根和周围的牙槽骨，其中含有组织特异性干细胞，即牙周膜干细胞[5-7]。牙周膜干细胞在牙周膜、牙骨质和牙槽骨的微环境调节和组织稳态中发挥积极作用[8]。
促红细胞生成素受体（erythropoietin receptor，EPOR）是Ⅰ型细胞因子受体家族的成员，表达于红系祖细胞表面[9-11]，其配体促红细胞生成素（erythropoietin，EPO）是一种由肾脏分泌的N-连接糖蛋白激素，可作用于红系祖细胞，并介导促红细胞生成素受体/Janus激酶/信号转导及转录激活因子5（signal transducer and activator of transcription 5，STAT5）通路的激活，从而促进骨髓造血[12-13]。近年来研究发现，促红细胞生成素/促红细胞生成素受体信号通路也参与调节非造血组织，如脑、心脏、骨骼肌、脂肪组织等的代谢反应[14-16]。ZHENG等[17-18]报道了促红细胞生成素通过激活Wnt/β-catenin信号通路加速体外牙周膜干细胞的生物矿化过程；给予促红细胞生成素治疗还可减轻高糖状态下受损的牙周膜干细胞氧化应激反应[19]。该研究旨在探讨促红细胞生成素/促红细胞生成素受体信号通路对牙周膜干细胞成骨分化的作用机制，为临床治疗提供新思路。
1　材料和方法　Materials and methods
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1.1　设计
体外细胞学实验。单因素方差分析和SNK事后检验，Student's t检验。
1.2　时间及地点
实验于2022年10月至2024年5月在山西医科大学第二医院中心实验室完成。
1.3　材料
1.3.1　前磨牙样本
收集2022年2-10月在山西医科大学第二医院口腔科就诊且因牙周病需拔除牙齿或进行牙周手术的25例患者前磨牙为疾病组，同时取正畸治疗需拔除牙齿的25例患者健康前磨牙为健康组。
疾病组纳入标准：①年龄20-58岁；②确诊为牙周炎，探诊深度≥7 mm，临床附着丧失≥5 mm，牙龈出血指数≥2；③临床资料完善。
疾病组排除标准：①心脑血管疾病或肝肾功能障碍；②近3个月有牙周治疗史；③近3个月使用消炎药、抗生素和免疫抑制剂；④认知障碍或精神异常者。
健康组纳入标准：①年龄20-58岁；②口腔卫生良好，牙石指数=0，牙龈无肿胀、出血。
健康组排除标准：①使用正畸矫正器；②近3个月使用消炎药、抗生素和免疫抑制剂；③妊娠和哺乳；④近2个月内连续使用含抗菌剂的漱口水；⑤心脑血管疾病或肝肾功能障碍；⑥认知障碍或精神异常者。
受试者均已签署知情同意书，由山西医科大学第二医院医学伦理委员会审查和批准，批准号为[2021]YX第343号。
1.3.2　主要试剂
促红细胞生成素（MedChemExpress，美国）；多能干细胞碱性磷酸酶显色试剂盒、茜素红S染色液（索莱宝，北京）；成骨诱导分化培养基、成脂诱导分化培养基（普诺赛，武汉）；Opti-MEM培养基、MEM培养基、胎牛血清（Gibco，美国）；实时荧光定量PCR试剂盒（诺维赞，南京）；Trizol、Lipofectamine 3000试剂盒（Thermo，美国）；促红细胞生成素受体小干扰RNA（small interfering RNA-EPOR，si-EPOR）及其阴性对照（si-NC）、si-STAT5及阴性对照si-NC（吉玛基因，上海）；鼠单克隆抗体β-actin（ab7817）、兔单克隆抗体促红细胞生成素受体（ab275686）、鼠单克隆抗体基质细胞抗原1（ab214086）、兔单克隆抗体CD146（ab75769）、兔单克隆抗体CD45（ab40763）、兔单克隆抗体磷酸化STAT5（p-STAT5，ab32364）、鼠单克隆抗体STAT5（ab230670）、鼠单克隆抗体CD31（ab9498）（Abcam，美国）。
1.4　方法
1.4.1　牙周膜干细胞分离与培养
离体牙放入预冷的MEM培养基中，采用含5%双抗的PBS反复冲洗离体牙，待清除血块后，用无菌刀片剥离距牙根1/3处的牙周膜组织[20]，PBS冲洗3次后，将组织置于3 mg/mL Ⅰ型胶原酶中，37 ℃消化60 min，将消化后的组织块重悬于3 mL MEM培养液，于37 ℃、体积分数5% CO2培养箱培养，每3 d更换1次培养液，7-14 d可见长梭形样细胞从组织块中爬出，当细胞融合度约70%时，采用0.25%胰酶消化并传代，培养的第4代细胞用于后续实验。
1.4.2　牙周膜干细胞流式鉴定
第4代牙周膜干细胞经0.25%胰酶消化后，用预冷PBS洗涤3次，PBS重悬细胞，4 ℃静置30 min，分成5组，向各组细胞中分别加入5 μL细胞表面标志物抗体（STRO-1、CD146、CD45、CD31、空白对照PBS）[21]，混匀后4 ℃避光孵育1 h；PBS洗涤2次，离心去上清，用预冷的500 μL PBS悬浮细胞，上流式细胞仪检测。
1.4.3　牙周膜干细胞成骨诱导
第4代牙周膜干细胞以1×105 L-1细胞浓度种于6孔板，每孔1.5 mL，培养48 h后更换为成骨诱导分化培养基（包含体积分数10%胎牛血清、1%青链霉素、1%谷氨酰胺、0.2%抗坏血酸、1% β-甘油磷酸钠、0.01%地塞米松、DMEM高糖培养基）[22]，成骨诱导7 d进行碱性磷酸酶染色，成骨诱导21 d进行茜素红染色。
1.4.4　牙周膜干细胞成脂诱导
第4代牙周膜干细胞以1×105 L-1细胞浓度种于6孔板，每孔1.5 mL，培养48 h后更换为成脂诱导分化培养基（包含体积分数10%胎牛血清、1%青链霉素、1 μmol/L地塞米松、200 μmol/L吲哚美辛、10 μg/mL胰岛素、0.5 mmol/L 3-异丁基-1-甲基黄嘌呤、DMEM高糖培养基）[23]，成脂诱导18 d进行油红O染色。
1.4.5　细胞分组与转染
第4代对数生长期的牙周膜干细胞以1×105 L-1细胞浓度接种于6孔板，每孔1.5 mL，待细胞培养至融合度70%，未转染细胞采用成骨诱导分化培养基诱导7 d或21 d，采用成脂诱导分化培养基诱导18 d后，采用100 ng/mL促红细胞生成素干预0，15，30，60，120 min。需转染细胞采用Opti-MEM培养基分别稀释Lipofectamine 3000试剂、si-NC/si-EPOR、si-NC/si-STAT5，将1 μg siRNA与50 μL Opti-MEM培养基混合，颠倒混匀，室温放置5 min，将1 μL Lipofectamine 3000、1 μL助转染试剂与50 μL Opti-MEM混合，混匀后室温放置5 min。将两种混合物再混合后逐滴加入每孔细胞中，同时每孔再加900 μL Opti-MEM培养基，转染6 h后，更换为1 mL完全培养基，继续培养48 h后，进行如下处理：①转染si-NC/si-EPOR后，采用成骨诱导分化培养基诱导7 d或21 d进行碱性磷酸酶染色、茜素红染色，采用成脂诱导分化培养基诱导18 d进行油红O染色；②转染si-NC/si-EPOR后，采用100 ng/mL促红细胞生成素干预5 d；③共转染si-NC/si-EPOR或si-NC/si-STAT5后，采用100 ng/mL促红细胞生成素干预5 d。qRT-PCR检测促红细胞生成素受体、Runt相关转录因子2、骨钙素、骨桥素和骨唾液蛋白mRNA表达水平；免疫印迹实验检测促红细胞生成素受体、p-STAT5、STAT5蛋白表达水平。
1.4.6　数据收集及筛选差异表达基因
从基因表达综合数据库（gene expression omnibus，GEO）下载了基因表达数据，获取和应用方法符合各数据库的指南和政策。数据集GSE16134和GSE10334基于GPL570平台，由Affymetrix Human Gene 2.0 ST Array处理，GSE16134包含241例牙周患者和69名健康人群，数据集GSE10334包含183例牙周患者和64名健康人群。利用R studio软件（版本4.2.3）limma软件包分析差异表达基因，以P < 0.05和logFC绝对值> 1.5进行筛选。
1.5　主要观察指标
1.5.1　免疫印迹实验检测蛋白表达水平
经转染siRNA或采用促红细胞生成素处理的细胞，弃去培养基，PBS洗2遍，每孔加入100 μL细胞裂解液刮下细胞，移入新的1.5 mL EP管中，冰上裂解30 min，4 ℃、12 000 r/min离心20 min，取上清与6 x loading buffer涡旋混匀，98 ℃ 15 min使蛋白变性，经10% SDS-PAGE胶分离蛋白后，湿转法将蛋白转移到PVDF膜，转膜条件为300 mA，2 h，用含5% BSA的TBST封闭液室温孵育1 h，加入一抗（促红细胞生成素受体，1∶1 000；p-STAT5，1∶1 000；STAT5，1∶1 000），4 ℃孵育过夜，次日加入二抗（1∶5 000稀释），室温孵育2 h，采用ECL发光液发光，用Image J软件分析条带灰度值，以β-actin为内参，计算目的基因灰度值/β-actin灰度值，比值代表蛋白相对表达量。
1.5.2　碱性磷酸酶染色检测细胞成骨分化能力
采用多能干细胞碱性磷酸酶显色试剂盒，牙周膜干细胞经40 g/L多聚甲醛室温固定30 min，PBS冲洗3次后，加入显色缓冲液避光孵育30 min，用蒸馏水洗涤3次后，显微镜下观察拍照。用Image J软件统计胞浆内出现蓝色沉淀的阳性细胞个数，计算阳性率。
1.5.3　茜素红染色检测细胞成骨分化能力
牙周膜干细胞去除培养液，加入40 g/L多聚甲醛室温固定30 min，PBS冲洗3次后，加入2%茜素红S染色液室温孵育10 min，显微镜下观察拍照，然后每孔加入10%氯化十六烷基吡啶溶解后，酶标仪检测562 nm波长处吸光度值，每个样本设置3个复孔，计算平均值。
1.5.4　油红O染色检测细胞成脂分化能力
牙周膜干细胞去除培养液，加入40 g/L多聚甲醛室温孵育30 min，PBS冲洗3次后，采用60%异丙醇溶液平衡2次，每次5 min，配置0.3%油红O染色液并过滤，37 ℃避光染色60 min，用60%异丙醇溶液分化以停止染色，纯水洗净多余染料，显微镜下观察拍照，用Image J软件分析统计阳性染色面积。
1.5.5　qRT-PCR检测基因表达水平
采用1 mL Trizol裂解细胞，然后加入200 μL氯仿，剧烈振荡10 s，4 ℃、12 000 r/min离心10 min，吸出上层水相400 μL移入新的无酶EP管中，加400 μL异丙醇，4 ℃、12 000 r/min离心10 min，弃上清，加入1 mL体积分数75%乙醇，4 ℃、7 500 r/min离心5 min，弃上清，空气中晾干至沉淀块由白色转为半透明时加入无RNA酶水50 μL溶解RNA。将RNA反转录合成cDNA，以此为模板，采用qRT-PCR检测促红细胞生成素受体及成骨标志基因Runt相关转录因子2、骨钙素、骨桥素、骨唾液蛋白的表达水平。以β-actin为内参，采用2-ΔΔCt法计算相对表达量。引物序列见表1。
1.6　统计学分析
利用GraphPad Prism 8.0进行数据分析及作图，符合正态分布的计量资料以的形式表示，多组间数据比较采用单因素方差分析（ANOVA），两组间比较采用Student's t检验。图像资料用Image J（NIH）软件分析。以P < 0.05为差异有显著性意义。该研究统计学方法已经通过山西医科大学第二医院生物统计学专家审核。
2　结果　Results
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2.1　牙周膜干细胞鉴定结果
流式细胞仪检测结果显示，健康组牙周膜干细胞阳性表达间充质干细胞表面标记物STRO-1（31.52%）、CD146（67.19%）；阴性表达血小板内皮细胞标记物CD31（0.54%）及白细胞共同抗原CD45（1.37%），见图1A-D。细胞经成骨诱导7，21 d后，碱性磷酸酶染色和茜素红染色结果显示，与对照组相比，诱导后牙周膜干细胞成骨分化能力增强（图1E）；细胞经成脂诱导18 d后，油红O染色结果显示，与对照组相比，诱导后牙周膜干细胞脂滴增多（图1F），表明牙周膜干细胞具备多向分化潜能，显示出良好的干细胞特性。
2.2　促红细胞生成素受体在疾病组及对照组牙周膜干细胞中的表达
通过对GEO数据库GSE16134和GSE10334数据集的分析发现，牙周手术患者感染组织中促红细胞生成素受体的表达低于未感染组织，牙周炎牙龈组织中促红细胞生成素受体的表达低于健康人群（图2A，B，P < 0.01）。采用qRT-PCR和免疫印迹法检测分离培养的健康组及疾病组牙周膜干细胞中促红细胞生成素受体的mRNA和蛋白水平，结果显示，疾病组牙周膜干细胞中促红细胞生成素受体的mRNA和蛋白水平显著低于健康组牙周膜干细胞（图2C，D，P < 0.01）。
2.3　敲低促红细胞生成素受体抑制牙周膜干细胞成骨分化
在健康组牙周膜干细胞中分别转染si-NC或si-EPOR，经免疫印迹法和qRT-PCR检测验证促红细胞生成素受体敲低成功（图3A，B，P < 0.05）。成骨诱导培养7 d后碱性磷酸酶染色以及成骨诱导21 d后茜素红染色结果显示，敲低促红细胞生成素受体抑制牙周膜干细胞的成骨分化能力（图3C，P < 0.05）。qRT-PCR结果显示，与si-NC组相比，si-EPOR组Runt相关转录因子2、骨钙素、骨桥素和骨唾液蛋白的表达水平显著降低（图3D，P < 0.05）。
2.4　促红细胞生成素对牙周膜干细胞成骨分化的影响
qRT-PCR结果表明，促红细胞生成素处理后，疾病组牙周膜干细胞中促红细胞生成素受体表达恢复（图4A，P < 0.05），使用si-EPOR敲低促红细胞生成素受体后再给予促红细胞生成素处理，同样逆转了促红细胞生成素受体的表达水平（图4B，P < 0.01）。茜素红染色结果显示，促红细胞生成素处理后，提升了疾病组牙周膜干细胞成骨分化能力，以及成骨标志基因Runt相关转录因子2的表达水平（图4C-E，P < 0.05），提示促红细胞生成素通过诱导促红细胞生成素受体表达增加，促进牙周膜干细胞成骨分化。
2.5　促红细胞生成素诱导牙周膜干细胞中STAT5的磷酸化，促进成骨分化
蛋白质免疫印迹实验结果显示，随着促红细胞生成素处理时间的延长，疾病组牙周膜干细胞中STAT5磷酸化水平增加（图5A，P < 0.01）。qRT-PCR结果显示，使用si-STAT5沉默STAT5表达后，抑制了促红细胞生成素诱导的Runt相关转录因子2和骨钙素表达水平的增多（图5B，C，P < 0.05），提示促红细胞生成素通过诱导STAT5的磷酸化，恢复病理性牙周膜干细胞的成骨分化能力。
3　讨论　Discussion
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牙周膜干细胞具有自我更新和多向分化潜能，可分化为成骨细胞、脂肪细胞和软骨细胞，是再生医学中各类型组织修复的重要细胞来源[24-26]。在实验过程中，从健康人群和牙周炎患者前磨牙分离培养的牙周膜干细胞具有成骨及成脂分化潜能。近年来研究发现，牙周膜干细胞促进了牙周附着组织的再生、修复，在牙周骨缺损修复及牙周样组织形成中发挥重要作用，牙周膜祖细胞和牙周膜干细胞自体移植是牙周炎患者牙槽骨修复的一种治疗途径[27]。但由于牙周炎患者健康的牙周膜干细胞有限，病理性牙周膜干细胞成为自体牙周细胞治疗的候选细胞[28]。同时，SONODA等[29]研究表明可通过药理学方法恢复病理性组织干细胞的受损功能。
重组促红细胞生成素多用于治疗慢性肾脏病和癌症患者的继发性贫血，而促红细胞生成素/促红细胞生成素受体信号通路在调节神经祖细胞存活、增殖和分化过程中发挥重要作用[30-32]。研究发现，外源性促红细胞生成素恢复了病理性牙周膜干细胞的促红细胞生成素受体表达，并逆转了牙周炎患者牙周膜干细胞成骨分化能力的降低，增强了疾病特异性组织干细胞的功能，这在骨髓间充质干细胞中也有所体现。YAMAZA等[33]研究发现，在骨髓间充质干细胞中激活促红细胞生成素/促红细胞生成素受体/STAT5信号通路，恢复了皮下异位移植间充质干细胞后的造血功能。此外，促红细胞生成素受体信号通路作为一种微环境调节剂，对牙周膜干细胞的旁分泌有重要的调节作用[34-36]。
促红细胞生成素受体/STAT5信号通路在体内造血干细胞和红系祖细胞的微环境调节中具有重要意义[37-39]。STAT5作为各种细胞因子、激素和生长因子激活的转录因子，其活化后转位到细胞核中，调节靶基因的转录，影响多个生物学过程[40]。然而，促红细胞生成素/促红细胞生成素受体/STAT5信号通路在非造血干细胞（如间充质干细胞）中的作用尚不清楚。此研究在牙周膜干细胞中沉默促红细胞生成素受体的表达，抑制了牙周膜干细胞的成骨分化能力。BULUT等[41]研究发现，促红细胞生成素通过诱导STAT5磷酸化，负反馈调节泛素化介导的内吞作用，进而抑制红细胞表面促红细胞生成素受体的表达，提出促红细胞生成素受体下调做为一种防御机制，以对抗受体信号传导引起的细胞过度增殖。此研究提出了促红细胞生成素受体的另一种正反馈调节机制，在病理环境中恢复组织干细胞的功能，即促红细胞生成素刺激诱导了病理性牙周膜干细胞中促红细胞生成素受体mRNA和蛋白水平升高，增加STAT5磷酸化，上调成骨标志基因Runt相关转录因子2的表达水平，从而促进病理性牙周膜干细胞成骨分化能力的恢复。
但由于研究局限于细胞水平，促红细胞生成素/促红细胞生成素受体/STAT5信号通路在牙周疾病中的具体作用还需进一步在动物水平加以验证。
综上所述，通过基因沉默和配体诱导激活调控促红细胞生成素受体，证明了促红细胞生成素/促红细胞生成素受体对牙周膜干细胞成骨分化的重要作用，发现促红细胞生成素通过诱导STAT5的磷酸化，恢复病理性牙周膜干细胞的成骨分化能力，为牙周病的临床治疗提供了一种新思路。
基金
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  • 山西省重点研发计划项目(201903D321141)
  • 山西省卫生健康委科研课题项目
文献
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2025年第29卷第36期
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doi: 10.12307/2025.561
  • 接收时间：2024-06-14
  • 首发时间：2026-04-02
  • 出版时间：2025-12-28
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  • 收稿日期：2024-06-14
  • 修回日期：2024-11-11
  • 录用日期：2024-09-21
基金
Shanxi Provincial Key Research & Development Project(201903D321141)
山西省重点研发计划项目(201903D321141)
Shanxi Provincial Health Commission Research Project
山西省卫生健康委科研课题项目
作者信息
    山西医科大学第二医院口腔科，山西省太原市　030000
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https://castjournals.cast.org.cn/joweb/zgzzgcyj/CN/10.12307/2025.561
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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