PDGF信号在新生小鼠心脏再生过程中的作用及其机制研究
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摘要
急性心肌梗死可导致心肌细胞在短时间内大量丢失,并最终导致心脏功能减退,乃至心力衰竭的发生。以快速补给心肌细胞为目标的心血管再生医学一直以来都是医学界关注的热点。有研究显示,斑马鱼和蝾螈等低等脊椎动物的心脏切除15-20%心室后能够实现自我修复和完美再生。在此基础上,最近的研究提示,出生1天的新生小鼠心尖切除后也表现与斑马鱼类似的心脏再生现象,但出生后7天小鼠心尖切除后不能再生,转而疤痕修复,提示哺乳动物的心肌在出生后早期也具有增殖能力,但其增殖能力迅速丧失使其在成年期不能完全应对心脏的损伤。揭示调控心脏再生过程中的关键分子机制,对于开辟促进心肌再生的有效手段具有重要的理论价值。
有报道指出,斑马鱼心脏损伤后再生过程中,血小板源性生长因子(Platelet derived growth factor, PDGF)信号对心肌细胞增殖发挥了重要作用。最新的研究则显示,小鼠胰腺再生过程中,PDGF信号通过Ezh2调控胰腺β细胞增殖。鉴于PDGF信号在小鼠胰腺再生和斑马鱼心脏再生中的作用,我们推测该信号在新生小鼠心尖切除损伤后心脏再生过程中可能发挥了重要作用。为了验证这一假设,我们在动物实验水平检测PDGF信号与新生小鼠的心脏再生的关系；继而在细胞水平进一步探讨PDGF信号促进心肌细胞增殖的具体机制、关键分子和通路。
主要的研究结果如下：
第—部分：PDGF信号相关分子在出生后小鼠心脏发育过程中的表达变化
目的：检测PDGF相关分子在出生后小鼠心脏发育过程中的表达变化。方法：Real time PCR检测小鼠出生后心脏发育过程中PDGF相关基因和Ezh2相关基因的表达变化,Western blot实验检测PDGF受体(Platelet Derived Growth FactorReceptor, PDGFR)和Ezh2的蛋白水平变化,免疫荧光染色高内涵扫描检测小鼠出生后心脏增殖能力的变化。
结果：小鼠出生后心脏发育过程中PDGFA和PDGFB的表达量在4-7天达到高峰,之后逐渐下降,PDGF受体β(Platelet Derived Growth Factor Receptor beta, PDGFRB)的表达量在出生后逐渐下降。Ezh2的表达量在出生后4天达到高峰,之后逐渐下降,至成年期不表达。Suz12和Eed的表达量变化趋势与Ezh2相似。细胞周期抑制因子p16和p19在出生后表达升高,而CDKN2B在出生后表达量逐渐降低。
结论：小鼠出生后心脏发育过程中,在出生4天出现增殖高峰,出生7天后增殖能力急剧下降。小鼠出生后PDGF相关分子和Ezh2相关分子的表达量变化与其增殖能力的变化相一致,可能与增殖能力的调控相关,但其确切的关系需要进一步实验证实。
第二部分：PDGF信号相关分子在新生小鼠心脏再生过程中的表达变化
目的：检测PDGF信号是否参与新生小鼠心脏再生的过程。
方法：构建新生小鼠心尖切除术后心脏再生模型,real time PCR检测新生小鼠心脏再生过程中PDGF相关基因的表达变化,免疫组化和免疫荧光染色检测小鼠心脏再生过程中PDGFRBEzh2的分布。
结果：新生小鼠心尖切除后心脏再生,术后21天心脏超声显示心功能与Sham组相似。与Sham组相比,心尖切除组PDGF信号相关基因PDGFB, PDGFC, PDGFD, PDGFRB都发生了明显的变化,并且其时间点均在术后1天和4天。而免疫组化实验结果显示,PDGFRB在术后7天大量表达于切口处。Ezh2, Suzl2, Eed这些PRC2核心成员在新生小鼠心尖切除后再生过程中的表达发生了明显的变化,主要体现在术后1天,他们的表达量都发生了下降,之后再恢复到正常水平。而免疫荧光染色的研究发现,Ezh2的分布主要集中在再生区域。
结论：新生小鼠的心脏具有完全再生的能力,PDGF受体及Ezh2的表达在新生小鼠再生过程中发生了规律性变化。
第三部分：PDGF信号相关分子在心肌细胞中的作用
目的：在细胞水平探讨PDGF信号和Ezh2对心肌细胞的作用机制。
方法：标准培养H9C2心肌细胞,给予PDGF-BB刺激后高内涵细胞扫描分析细胞的增殖能力,流式细胞术检测细胞周期,real time PCR检测Ezh2和相关基因的表达变化,Western blot检测Ezh2的表达变化,siRNA沉默Ezh2后流式细胞术检测细胞周期和细胞凋亡,real time PCR检测Ezh2和相关基因的表达变化。siRNA沉默Ezh2并给予PDGF-BB刺激后高内涵细胞扫描分析细胞的增殖能力。Western blot检测相关通路的激活情况,抑制通路后Western blot检测相关蛋白。
结果：PDGF-BB对H9C2心肌细胞具有明显的促增殖作用,流式细胞术实验显示PDGF-BB能够促进心肌细胞进入细胞周期。我们发现,PDGF-BB对H9C2心肌细胞的促增殖过程中,Ezh2蛋白表达水平升高,CDKN2A的mRNA水平降低。siRNA沉默H9C2心肌细胞中的Ezh2,可导致CDKN2A的mRNA水平升高。流式细胞分析显示沉默Ezh2对细胞周期并没有影响,但细胞凋亡比例增加。高内涵细胞扫描分析显示,沉默Ezh2能阻碍PDGF-BB对H9C2心肌细胞的促增殖作用。在PDGF-BB的刺激作用下,PLCγ通路,PI3K/Akt通路和Erk１/2通路均发生了激活,阻断Erkl/2通路后,Ezh2的水平也发生了下降,而阻断Akt通路后,Ezh2的水平并不受影响。
结论：PDGF-BB对H9C2心肌细胞具有明显的促增殖作用并能促进Ezh2蛋白的表达。siRNA沉默Ezh2后,H9C2心肌细胞发生了早期凋亡,同时阻碍了PDGF-BB对H9C2心肌细胞的促增殖作用,说明Ezh2在PDGF信号促进心肌细胞增殖过程中起到关键作用。在PDGF-BB的刺激作用下,PLCγ通路,PI3K/Akt通路和Erkl/2通路均发生了激活,而Ezh2受Erkl/2通路调控。Ezh2可能是通过调控CDKN2A的表达,从而影响心肌细胞增殖而参与再生。
Acute myocaridial infarction causes loss of cardiomyocytes in a short time, and induces impaired heart function, even heart failure. Cardiac regenerative medicine targeting the restoration of cardiomyocyte is always the focus of medicine. A series of studies showed that zebrafish and salamanders can perform a wonderful cardiac regeneration after15-20%removal of heart ventricle. Recently a study showed that the neonatal mice can also regenerate the heart after apex resection, which is similar to the phenomenon of zebrafish heart. But the regenerative capacity of the neonatal mouse heart is lost within the first week of postnatal life. It will be important to determine the mechanisms of heart regeneration for enhancing the limited regenerative ability of adult mammal response to the injuries.
In the process of zebrafish heart regeneration after injury, PDGF signaling plays an important role in replicating the cardiomyocyte. Also, PDGF signaling regulates the pancreatic beta cell proliferation by Ezh2in mice pancreas regeneration. Due to the role of PDGF signaling in mice pancreas regeneration and zebrafish heart regeneration, we hypothesis PDGF signaling may be involved in neonatal mice heart regeneration after apex resection. To test the hypothesis, we determined whether the PDGF signaling is involved in neonatal mice heart regeneration in vivo, and investigate the detailed mechanisms, key molecules and pathways which is involved in promoting cardiomyocyte proliferation by PDGF signaling in vitro.
The main findings are as follows:
The first part:The expression changes of PDGF signaling related genes in the postnatal mice heart development
Objective:To observe the expression of PDGF related genes in the mice heart development after birth.
Methods:real time-PCR was used to detect the expression of PDGF related genes and Ezh2related genes in the mice heart development after birth. The protein levels of PDGF receptors and Ezh2were detected by Western blot. The mice heart proliferative ability after birth was investigated by high content screening.
Results:The mice heart maintained the proliferative ability within a week after birth, and the peak appeared at postnatal4days, but the proliferative ability lost after7days postnatally. The expression of PDGFA and PDGFB peaked at4-7days during the postnatal development, and then gradually decreased. The expression of PDGFRB decreased after birth. The expression of Ezh2reached a peak at postnatal4days, and gradually declined to the undetected level in the adulthood. The expression of Suz12and Eed were similar to that of Ezh2. The expressions of cell cycle inhibitor p16and p19were increased after birth, whereas the expression of CDKN2B decreased gradually in the postnatal period.
Conclusions:During the mice heart postnatal development, the proliferative ability reached a peak at4days after birth, and sharply declined after7days. The trends of PDGF related genes and Ezh2related genes were consistent with that of the proliferative ability, which is associated with the regulation of proliferative ability, but the exact relationship needs further confirmation.
The second part:The expression changes of PDGF signaling related genes in the neonatal mice heart regeneration
Objective:To detect whether PDGF signaling is involved in the process of newborn mice myocardial regeneration.
Methods:The heart regeneration model in newborn mice was constructed. The real time-PCR was used to detect the levels of gene associated with PDGF. The immunohistochemistry and immunofluorescence staining was used to detect the PDGFRB and Ezh2distribution in the process of newborn mice myocardial regeneration.
Results:The neonatal heart after apex resection was completely regenerated, with the similar results of cardiac function test between apex resection group and sham group. The levels of PDGF associated genes, such as PDGFB, PDGFC, PDGFD and PDGFRB were changed significantly, and the time were1day and4day post surgery. The immunohistochemistry showed the PDGFRB abundantly expressed at the incision in the seven days after surgery. The levels of PRC2core members, such as Ezh2, Suzl2and Eed were changed significantly, and the time is1day post surgery. The immunohistochemistry showed the Ezh2abundantly expressed in the regenerating area.
Conclusion:The newborn mice have the ability to completely regenerate the heart. The expression of PDGF receptor and Ezh2changed regularly in the regenerative response after apex resection in the newborn.
The third part:The effect of PDGF related genes on cardiomyocyte
Objective:To investigate the specific role of PDGF signaling and Ezh2in cardiomyocytes.
Methods:H9C2cell line was cultured in standard. Cell was stimulated by PDGF-BB following high content cell analysis. Flow cytometry was used to detect the cell cycle phases. Real time-PCR was used to detect the level of Ezh2and relative genes. Western blot was used to detect the change of Ezh2protein. After Ezh2knockdown by siRNA, flow cytometry was used to detect the cell phases and apoptosis.Real time-PCR was used to detect the level of Ezh2and relative genes.
Results:PDGF-BB had a growth-promoting effect on H9C2cardiomyocytes. Flow cytometry showed H9C2cardiomyocytes reentered the cell cycle under the PDGF-BB stimulation. In the process of H9C2myocardial cell proliferation, the protein level of Ezh2was increased with the declining level of CDKN2A. When Ezh2was knockdown by siRNA, the level of CDKN2A elevated. The cell cycle was not affected by the knockdown of Ezh2, but the apoptosis occurred. Ezh2knockdown eliminated the proliferation effect of PDGF-BB on H9C2myocardial cells. Under the stimulation of PDGF-BB, PLCy pathway, PI3K/Akt pathway and Erkl/2pathway were activated. The level of Ezh2decreased under the blocking of Erkl/2pathway, but the blocking of Akt pathway did not affect the level of Ezh2.
Conclusion:PDGF-BB had a growth-promoting effect on H9C2cardiomyocytes, and increased the level of Ezh2. After knockdown of Ezh2, H9C2cells showed apoptosis, and affected the proliferation effect of PDGF-BB. Under the stimulation of PDGF-BB, many pathways were activated, but the Ezh2was under the control of Erkl/2pathway. Ezh2performed its function by regulating the level of CDKN2A, which could be involved in heart regeneration.
有报道指出,斑马鱼心脏损伤后再生过程中,血小板源性生长因子(Platelet derived growth factor, PDGF)信号对心肌细胞增殖发挥了重要作用。最新的研究则显示,小鼠胰腺再生过程中,PDGF信号通过Ezh2调控胰腺β细胞增殖。鉴于PDGF信号在小鼠胰腺再生和斑马鱼心脏再生中的作用,我们推测该信号在新生小鼠心尖切除损伤后心脏再生过程中可能发挥了重要作用。为了验证这一假设,我们在动物实验水平检测PDGF信号与新生小鼠的心脏再生的关系；继而在细胞水平进一步探讨PDGF信号促进心肌细胞增殖的具体机制、关键分子和通路。
主要的研究结果如下：
第—部分：PDGF信号相关分子在出生后小鼠心脏发育过程中的表达变化
目的：检测PDGF相关分子在出生后小鼠心脏发育过程中的表达变化。方法：Real time PCR检测小鼠出生后心脏发育过程中PDGF相关基因和Ezh2相关基因的表达变化,Western blot实验检测PDGF受体(Platelet Derived Growth FactorReceptor, PDGFR)和Ezh2的蛋白水平变化,免疫荧光染色高内涵扫描检测小鼠出生后心脏增殖能力的变化。
结果：小鼠出生后心脏发育过程中PDGFA和PDGFB的表达量在4-7天达到高峰,之后逐渐下降,PDGF受体β(Platelet Derived Growth Factor Receptor beta, PDGFRB)的表达量在出生后逐渐下降。Ezh2的表达量在出生后4天达到高峰,之后逐渐下降,至成年期不表达。Suz12和Eed的表达量变化趋势与Ezh2相似。细胞周期抑制因子p16和p19在出生后表达升高,而CDKN2B在出生后表达量逐渐降低。
结论：小鼠出生后心脏发育过程中,在出生4天出现增殖高峰,出生7天后增殖能力急剧下降。小鼠出生后PDGF相关分子和Ezh2相关分子的表达量变化与其增殖能力的变化相一致,可能与增殖能力的调控相关,但其确切的关系需要进一步实验证实。
第二部分：PDGF信号相关分子在新生小鼠心脏再生过程中的表达变化
目的：检测PDGF信号是否参与新生小鼠心脏再生的过程。
方法：构建新生小鼠心尖切除术后心脏再生模型,real time PCR检测新生小鼠心脏再生过程中PDGF相关基因的表达变化,免疫组化和免疫荧光染色检测小鼠心脏再生过程中PDGFRBEzh2的分布。
结果：新生小鼠心尖切除后心脏再生,术后21天心脏超声显示心功能与Sham组相似。与Sham组相比,心尖切除组PDGF信号相关基因PDGFB, PDGFC, PDGFD, PDGFRB都发生了明显的变化,并且其时间点均在术后1天和4天。而免疫组化实验结果显示,PDGFRB在术后7天大量表达于切口处。Ezh2, Suzl2, Eed这些PRC2核心成员在新生小鼠心尖切除后再生过程中的表达发生了明显的变化,主要体现在术后1天,他们的表达量都发生了下降,之后再恢复到正常水平。而免疫荧光染色的研究发现,Ezh2的分布主要集中在再生区域。
结论：新生小鼠的心脏具有完全再生的能力,PDGF受体及Ezh2的表达在新生小鼠再生过程中发生了规律性变化。
第三部分：PDGF信号相关分子在心肌细胞中的作用
目的：在细胞水平探讨PDGF信号和Ezh2对心肌细胞的作用机制。
方法：标准培养H9C2心肌细胞,给予PDGF-BB刺激后高内涵细胞扫描分析细胞的增殖能力,流式细胞术检测细胞周期,real time PCR检测Ezh2和相关基因的表达变化,Western blot检测Ezh2的表达变化,siRNA沉默Ezh2后流式细胞术检测细胞周期和细胞凋亡,real time PCR检测Ezh2和相关基因的表达变化。siRNA沉默Ezh2并给予PDGF-BB刺激后高内涵细胞扫描分析细胞的增殖能力。Western blot检测相关通路的激活情况,抑制通路后Western blot检测相关蛋白。
结果：PDGF-BB对H9C2心肌细胞具有明显的促增殖作用,流式细胞术实验显示PDGF-BB能够促进心肌细胞进入细胞周期。我们发现,PDGF-BB对H9C2心肌细胞的促增殖过程中,Ezh2蛋白表达水平升高,CDKN2A的mRNA水平降低。siRNA沉默H9C2心肌细胞中的Ezh2,可导致CDKN2A的mRNA水平升高。流式细胞分析显示沉默Ezh2对细胞周期并没有影响,但细胞凋亡比例增加。高内涵细胞扫描分析显示,沉默Ezh2能阻碍PDGF-BB对H9C2心肌细胞的促增殖作用。在PDGF-BB的刺激作用下,PLCγ通路,PI3K/Akt通路和Erk１/2通路均发生了激活,阻断Erkl/2通路后,Ezh2的水平也发生了下降,而阻断Akt通路后,Ezh2的水平并不受影响。
结论：PDGF-BB对H9C2心肌细胞具有明显的促增殖作用并能促进Ezh2蛋白的表达。siRNA沉默Ezh2后,H9C2心肌细胞发生了早期凋亡,同时阻碍了PDGF-BB对H9C2心肌细胞的促增殖作用,说明Ezh2在PDGF信号促进心肌细胞增殖过程中起到关键作用。在PDGF-BB的刺激作用下,PLCγ通路,PI3K/Akt通路和Erkl/2通路均发生了激活,而Ezh2受Erkl/2通路调控。Ezh2可能是通过调控CDKN2A的表达,从而影响心肌细胞增殖而参与再生。
Acute myocaridial infarction causes loss of cardiomyocytes in a short time, and induces impaired heart function, even heart failure. Cardiac regenerative medicine targeting the restoration of cardiomyocyte is always the focus of medicine. A series of studies showed that zebrafish and salamanders can perform a wonderful cardiac regeneration after15-20%removal of heart ventricle. Recently a study showed that the neonatal mice can also regenerate the heart after apex resection, which is similar to the phenomenon of zebrafish heart. But the regenerative capacity of the neonatal mouse heart is lost within the first week of postnatal life. It will be important to determine the mechanisms of heart regeneration for enhancing the limited regenerative ability of adult mammal response to the injuries.
In the process of zebrafish heart regeneration after injury, PDGF signaling plays an important role in replicating the cardiomyocyte. Also, PDGF signaling regulates the pancreatic beta cell proliferation by Ezh2in mice pancreas regeneration. Due to the role of PDGF signaling in mice pancreas regeneration and zebrafish heart regeneration, we hypothesis PDGF signaling may be involved in neonatal mice heart regeneration after apex resection. To test the hypothesis, we determined whether the PDGF signaling is involved in neonatal mice heart regeneration in vivo, and investigate the detailed mechanisms, key molecules and pathways which is involved in promoting cardiomyocyte proliferation by PDGF signaling in vitro.
The main findings are as follows:
The first part:The expression changes of PDGF signaling related genes in the postnatal mice heart development
Objective:To observe the expression of PDGF related genes in the mice heart development after birth.
Methods:real time-PCR was used to detect the expression of PDGF related genes and Ezh2related genes in the mice heart development after birth. The protein levels of PDGF receptors and Ezh2were detected by Western blot. The mice heart proliferative ability after birth was investigated by high content screening.
Results:The mice heart maintained the proliferative ability within a week after birth, and the peak appeared at postnatal4days, but the proliferative ability lost after7days postnatally. The expression of PDGFA and PDGFB peaked at4-7days during the postnatal development, and then gradually decreased. The expression of PDGFRB decreased after birth. The expression of Ezh2reached a peak at postnatal4days, and gradually declined to the undetected level in the adulthood. The expression of Suz12and Eed were similar to that of Ezh2. The expressions of cell cycle inhibitor p16and p19were increased after birth, whereas the expression of CDKN2B decreased gradually in the postnatal period.
Conclusions:During the mice heart postnatal development, the proliferative ability reached a peak at4days after birth, and sharply declined after7days. The trends of PDGF related genes and Ezh2related genes were consistent with that of the proliferative ability, which is associated with the regulation of proliferative ability, but the exact relationship needs further confirmation.
The second part:The expression changes of PDGF signaling related genes in the neonatal mice heart regeneration
Objective:To detect whether PDGF signaling is involved in the process of newborn mice myocardial regeneration.
Methods:The heart regeneration model in newborn mice was constructed. The real time-PCR was used to detect the levels of gene associated with PDGF. The immunohistochemistry and immunofluorescence staining was used to detect the PDGFRB and Ezh2distribution in the process of newborn mice myocardial regeneration.
Results:The neonatal heart after apex resection was completely regenerated, with the similar results of cardiac function test between apex resection group and sham group. The levels of PDGF associated genes, such as PDGFB, PDGFC, PDGFD and PDGFRB were changed significantly, and the time were1day and4day post surgery. The immunohistochemistry showed the PDGFRB abundantly expressed at the incision in the seven days after surgery. The levels of PRC2core members, such as Ezh2, Suzl2and Eed were changed significantly, and the time is1day post surgery. The immunohistochemistry showed the Ezh2abundantly expressed in the regenerating area.
Conclusion:The newborn mice have the ability to completely regenerate the heart. The expression of PDGF receptor and Ezh2changed regularly in the regenerative response after apex resection in the newborn.
The third part:The effect of PDGF related genes on cardiomyocyte
Objective:To investigate the specific role of PDGF signaling and Ezh2in cardiomyocytes.
Methods:H9C2cell line was cultured in standard. Cell was stimulated by PDGF-BB following high content cell analysis. Flow cytometry was used to detect the cell cycle phases. Real time-PCR was used to detect the level of Ezh2and relative genes. Western blot was used to detect the change of Ezh2protein. After Ezh2knockdown by siRNA, flow cytometry was used to detect the cell phases and apoptosis.Real time-PCR was used to detect the level of Ezh2and relative genes.
Results:PDGF-BB had a growth-promoting effect on H9C2cardiomyocytes. Flow cytometry showed H9C2cardiomyocytes reentered the cell cycle under the PDGF-BB stimulation. In the process of H9C2myocardial cell proliferation, the protein level of Ezh2was increased with the declining level of CDKN2A. When Ezh2was knockdown by siRNA, the level of CDKN2A elevated. The cell cycle was not affected by the knockdown of Ezh2, but the apoptosis occurred. Ezh2knockdown eliminated the proliferation effect of PDGF-BB on H9C2myocardial cells. Under the stimulation of PDGF-BB, PLCy pathway, PI3K/Akt pathway and Erkl/2pathway were activated. The level of Ezh2decreased under the blocking of Erkl/2pathway, but the blocking of Akt pathway did not affect the level of Ezh2.
Conclusion:PDGF-BB had a growth-promoting effect on H9C2cardiomyocytes, and increased the level of Ezh2. After knockdown of Ezh2, H9C2cells showed apoptosis, and affected the proliferation effect of PDGF-BB. Under the stimulation of PDGF-BB, many pathways were activated, but the Ezh2was under the control of Erkl/2pathway. Ezh2performed its function by regulating the level of CDKN2A, which could be involved in heart regeneration.
引文
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