Research progress in mesenchymal stem cells modified by Heme oxygenase 1_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

SUN Dong ¹ ,  SONG Hongli ² , SHEN Zhongyang ²

1. The First Central Clinical College, Tianjin Medical University, Tianjin, 300192, P.R.China;
2. Department of Organ Transplantation, Tianjin First Central Hospital, Tianjin Key Laboratory of Organ Transplantation, Key Laboratory of Transplantation Medicine, Chinese Academy of Medical Sciences, Tianjin, 300192, P.R.China;

Corresponding author：

SONG Hongli, Email: hlsong26@163.com

Keywords：

Mesenchymal stem cells; Heme oxygenase 1; anti-apoptosis; immunoregulation; research progress

DOI：

10.7507/1002-1892.201812079

Video：

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Objective To review the literature reports on research progress of Heme oxygenase 1 (HO-1) modified mesenchymal stem cells (MSCs). Methods The significance, effects, and related mechanism of HO-1 modification of MSCs were summarized by consulting the related literatures and reports of HO-1 modification of MSCs. Results HO-1 modification of MSCs has important research value. It can effectively enhance the anti-oxidative stress and anti-apoptotic properties of MSCs in complex internal environment after transplantation into vivo. It can also effectively enhance the immune regulation function of MSCs. It can improve the anti-injury, repair, and immune regulation effect of MSCs in various disease models and research fields. Conclusion The basic research of HO-1 modified MSCs has made remarkable progress, which is expected to be applied in clinical trials and provide theoretical basis and reference value for stem cell therapy.

Citation： SUN Dong, SONG Hongli, SHEN Zhongyang. Research progress in mesenchymal stem cells modified by Heme oxygenase 1. Chinese Journal of Reparative and Reconstructive Surgery, 2019, 33(7): 901-906. doi: 10.7507/1002-1892.201812079 Copy

1.	Volkman R, Offen D. Concise review: mesenchymal stem cells in neurodegenerative diseases. Stem Cells, 2017, 35(8): 1867-1880.
2.	郑伟伟, 杨民, 武成, 等. 滑膜间充质干细胞体内外成骨特性的实验研究. 中国修复重建外科杂志, 2016, 30(1): 102-109.
3.	de Souza LE, Malta TM, Kashima Haddad S, et al. Mesenchymal stem cells and pericytes: to what extent are they related? Stem Cells Dev, 2016, 25(24): 1843-1852.
4.	Gazdic M, Arsenijevic A, Markovic BS, et al. Mesenchymal stem cell-dependent modulation of liver diseases. Int J Biol Sci, 2017, 13(9): 1109-1117.
5.	Barakat M, Gabr MM, Zhran F, et al. Upregulation of heme oxygenase 1 (HO-1) attenuates kidney damage, oxidative stress and inflammatory reaction during renal ischemia/reperfusion injury. Gen Physiol Biophys, 2018, 37(2): 193-204.
6.	Agarwal A, Nick HS. Renal response to tissue injury: lessons from heme oxygenase-1 GeneAblation and expression. J Am Soc Nephrol, 2000, 11(5): 965-973.
7.	Loboda A, Damulewicz M, Pyza E, et al. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci, 2016, 73(17): 3221-3247.
8.	Lin R, Cai J, Kostuk EW, et al. Fumarate modulates the immune/inflammatory response and rescues nerve cells and neurological function after stroke in rats. J Neuroinflammation, 2016, 13(1): 269.
9.	Tomczyk M, Kraszewska I, Dulak J, et al. Modulation of the monocyte/macrophage system in heart failure by targeting heme oxygenase-1. Vascul Pharmacol, 2019, 112: 79-90.
10.	Even B, Fayad-Kobeissi S, Gagliolo JM, et al. Heme oxygenase-1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction. Aging Cell, 2018, 17(6): e12837.
11.	Jun SY, Hong SM, Bae YK, et al. Clinicopathological and prognostic significance of heme oxygenase-1 expression in small intestinal adenocarcinomas. Pathol Int, 2018, 68(5): 294-300.
12.	葛礼豪, 于德水, 苏瑞超, 等. 缺氧诱导因子 1α 对人羊膜间充质干细胞耐受缺氧能力影响的实验研究. 中国修复重建外科杂志, 2018, 32(3): 264-269.
13.	Liu N, Wang H, Han G, et al. Alleviation of apoptosis of bone marrow-derived mesenchymal stem cells in the acute injured kidney by heme oxygenase-1 gene modification. Int J Biochem Cell Biol, 2015, 69: 85-94.
14.	Cremers NA, Lundvig DM, van Dalen SC, et al. Curcumin-induced heme oxygenase-1 expression prevents H₂O₂-induced cell death in wild type and heme oxygenase-2 knockout adipose-derived mesenchymal stem cells. Int J Mol Sci, 2014, 15(10): 17974-17999.
15.	Patel SR, Copland IB, Garcia MA, et al. Human mesenchymal stromal cells suppress T-cell proliferation independent of heme oxygenase-1. Cytotherapy, 2015, 17(4): 382-391.
16.	Deramaudt TB, da Silva JL, Remy P, et al. Negative regulation of human heme oxygenase in microvessel endothelial cells by dexamethasone. Proc Soc Exp Biol Med, 1999, 222(2): 185-193.
17.	Wang X, Wang S, Zhou Y, et al. BM-MSCs protect against liver ischemia/reperfusion injury via HO-1 mediated autophagy. Mol Med Rep, 2018, 18(2): 2253-2262.
18.	Hamedi-Asl P, Halabian R, Bahmani P, et al. Adenovirus-mediated expression of the HO-1 protein within MSCs decreased cytotoxicity and inhibited apoptosis induced by oxidative stresses. Cell Stress Chaperones, 2012, 17(2): 181-190.
19.	Yu ZY, Ma D, He ZC, et al. Heme oxygenase-1 protects bone marrow mesenchymal stem cells from iron overload through decreasing reactive oxygen species and promoting IL-10 generation. Exp Cell Res, 2018, 362(1): 28-42.
20.	Tang YL, Tang Y, Zhang YC, et al. Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. J Am Coll Cardiol, 2005, 46(7): 1339-1350.
21.	Pan H, Guan D, Liu X, et al. SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Res, 2016, 26(2): 190-205.
22.	Davis C, Dukes A, Drewry M, et al. MicroRNA-183-5p increases with age in bone-derived extracellular vesicles, suppresses bone marrow stromal (stem) cell proliferation, and induces stem cell senescence. Tissue Eng Part A, 2017, 23(21-22): 1231-1240.
23.	Barbagallo I, Vanella A, Peterson SJ, et al. Overexpression of heme oxygenase-1 increases human osteoblast stem cell differentiation. J Bone Miner Metab, 2010, 28(3): 276-288.
24.	Vanella L, Kim DH, Asprinio D, et al. HO-1 expression increases mesenchymal stem cell-derived osteoblasts but decreases adipocyte lineage. Bone, 2010, 46(1): 236-243.
25.	Gu Q, Gu Y, Shi Q, et al. Hypoxia promotes osteogenesis of human placental-derived mesenchymal stem cells. Tohoku J Exp Med, 2016, 239(4): 287-296.
26.	Liu X, Ji C, Xu L, et al. Hmox1 promotes osteogenic differentiation at the expense of reduced adipogenic differentiation induced by BMP9 in C3H10T1/2 cells. J Cell Biochem, 2018, 119(7): 5503-5516.
27.	Shen ZY, Wu B, Liu T, et al. Immunomodulatory effects of bone marrow mesenchymal stem cells overexpressing heme oxygenase-1: Protective effects on acute rejection following reduced-size liver transplantation in a rat model. Cell Immunol, 2017, 313: 10-24.
28.	Zhang D, Fu L, Wang L, et al. Therapeutic benefit of mesenchymal stem cells in pregnant rats with angiotensin receptor agonistic autoantibody-induced hypertension: Implications for immunomodulation and cytoprotection. Hypertens Pregnancy, 2017, 36(3): 247-258.
29.	Suresh SC, Selvaraju V, Thirunavukkarasu M, et al. Thioredoxin-1(Trx1) engineered mesenchymal stem cell therapy increased pro-angiogenic factors, reduced fibrosis and improved heart function in the infarcted rat myocardium. Int J Cardiol, 2015, 201: 517-528.
30.	Shu T, Zeng B, Ren X, et al. HO-1 modified mesenchymal stem cells modulate MMPs/TIMPs system and adverse remodeling in infarcted myocardium. Tissue Cell, 2010, 42(4): 217-222.
31.	Wang J, Hu X, Jiang H. MSCs modified with HO-1 gene transplantation: A novel therapeutic approach for attenuating heart failure. Int J Cardiol, 2016, 214: 159-160.
32.	Zhang ZH, Zhu W, Ren HZ, et al. Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure. Stem Cell Res Ther, 2017, 8(1): 70.
33.	Chen X, Zhang Y, Wang W, et al. Mesenchymal stem cells modified with Heme oxygenase-1 have enhanced paracrine function and attenuate lipopolysaccharide-induced inflammatory and oxidative damage in pulmonary microvascular endothelial cells. Cell Physiol Biochem, 2018, 49(1): 101-122.
34.	Liu N, Wang H, Han G, et al. Enhanced proliferation and differentiation of HO-1 gene-modified bone marrow-derived mesenchymal stem cells in the acute injured kidney. Int J Mol Med, 2018, 42(2): 946-956.
35.	王绕绕, 宋红丽. 自噬在肝移植缺血再灌注损伤中的研究进展. 中华器官移植杂志, 2015, 36(9): 565-568.
36.	Wang Y, Wang JL, Ma HC, et al. Mesenchymal stem cells increase heme oxygenase 1-activated autophagy in treatment of acute liver failure. Biochem Biophys Res Commun, 2019, 508(3): 682-689.
37.	Wang R, Shen Z, Yang L, et al. Protective effects of heme oxygenase-1-transduced bone marrow-derived mesenchymal stem cells on reduced-size liver transplantation: Role of autophagy regulated by the ERK/mTOR signaling pathway. Int J Mol Med, 2017, 40(5): 1537-1548.
38.	Yu M, Wang J, Fang Q, et al. High expression of heme oxygenase-1 in target organs may attenuate acute graft-versus-host disease through regulation of immune balance of TH17/Treg. Transpl Immunol, 2016, 37: 10-17.
39.	Lee HS, Song S, Shin DY, et al. Enhanced effect of human mesenchymal stem cells expressing human TNF-αR-Fc and HO-1 gene on porcine islet xenotransplantation in humanized mice. Xenotransplantation, 2018, 25(1). doi: 10.1111/xen.12342.
40.	Wu B, Song HL, Yang Y, et al. Improvement of liver transplantation outcome by Heme oxygenase-1-transduced bone marrow mesenchymal stem cells in rats. Stem Cells Int, 2016, 2016: 9235073.
41.	Yang L, Shen ZY, Wang RR, et al. Effects of heme oxygenase-1-modified bone marrow mesenchymal stem cells on microcirculation and energy metabolism following liver transplantation. World J Gastroenterol, 2017, 23(19): 3449-3467.
42.	Yang Y, Song HL, Zhang W, et al. Heme oxygenase-1-transduced bone marrow mesenchymal stem cells in reducing acute rejection and improving small bowel transplantation outcomes in rats. Stem Cell Res Ther, 2016, 7(1): 164.
43.	Yin ML, Song HL, Yang Y, et al. Effect of CXCR3/HO-1 genes modified bone marrow mesenchymal stem cells on small bowel transplant rejection. World J Gastroenterol, 2017, 23(22): 4016-4038.
44.	Lee SH, Kim Y, Rhew D, et al. Effect of canine mesenchymal stromal cells overexpressing heme oxygenase-1 in spinal cord injury. J Vet Sci, 2017, 18(3): 377-386.
45.	Hou C, Shen L, Huang Q, et al. The effect of heme oxygenase-1 complexed with collagen on MSC performance in the treatment of diabetic ischemic ulcer. Biomaterials, 2013, 34(1): 112-120.

1. Volkman R, Offen D. Concise review: mesenchymal stem cells in neurodegenerative diseases. Stem Cells, 2017, 35(8): 1867-1880.
2. 郑伟伟, 杨民, 武成, 等. 滑膜间充质干细胞体内外成骨特性的实验研究. 中国修复重建外科杂志, 2016, 30(1): 102-109.
3. de Souza LE, Malta TM, Kashima Haddad S, et al. Mesenchymal stem cells and pericytes: to what extent are they related? Stem Cells Dev, 2016, 25(24): 1843-1852.
4. Gazdic M, Arsenijevic A, Markovic BS, et al. Mesenchymal stem cell-dependent modulation of liver diseases. Int J Biol Sci, 2017, 13(9): 1109-1117.
5. Barakat M, Gabr MM, Zhran F, et al. Upregulation of heme oxygenase 1 (HO-1) attenuates kidney damage, oxidative stress and inflammatory reaction during renal ischemia/reperfusion injury. Gen Physiol Biophys, 2018, 37(2): 193-204.
6. Agarwal A, Nick HS. Renal response to tissue injury: lessons from heme oxygenase-1 GeneAblation and expression. J Am Soc Nephrol, 2000, 11(5): 965-973.
7. Loboda A, Damulewicz M, Pyza E, et al. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci, 2016, 73(17): 3221-3247.
8. Lin R, Cai J, Kostuk EW, et al. Fumarate modulates the immune/inflammatory response and rescues nerve cells and neurological function after stroke in rats. J Neuroinflammation, 2016, 13(1): 269.
9. Tomczyk M, Kraszewska I, Dulak J, et al. Modulation of the monocyte/macrophage system in heart failure by targeting heme oxygenase-1. Vascul Pharmacol, 2019, 112: 79-90.
10. Even B, Fayad-Kobeissi S, Gagliolo JM, et al. Heme oxygenase-1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction. Aging Cell, 2018, 17(6): e12837.
11. Jun SY, Hong SM, Bae YK, et al. Clinicopathological and prognostic significance of heme oxygenase-1 expression in small intestinal adenocarcinomas. Pathol Int, 2018, 68(5): 294-300.
12. 葛礼豪, 于德水, 苏瑞超, 等. 缺氧诱导因子 1α 对人羊膜间充质干细胞耐受缺氧能力影响的实验研究. 中国修复重建外科杂志, 2018, 32(3): 264-269.
13. Liu N, Wang H, Han G, et al. Alleviation of apoptosis of bone marrow-derived mesenchymal stem cells in the acute injured kidney by heme oxygenase-1 gene modification. Int J Biochem Cell Biol, 2015, 69: 85-94.
14. Cremers NA, Lundvig DM, van Dalen SC, et al. Curcumin-induced heme oxygenase-1 expression prevents H₂O₂-induced cell death in wild type and heme oxygenase-2 knockout adipose-derived mesenchymal stem cells. Int J Mol Sci, 2014, 15(10): 17974-17999.
15. Patel SR, Copland IB, Garcia MA, et al. Human mesenchymal stromal cells suppress T-cell proliferation independent of heme oxygenase-1. Cytotherapy, 2015, 17(4): 382-391.
16. Deramaudt TB, da Silva JL, Remy P, et al. Negative regulation of human heme oxygenase in microvessel endothelial cells by dexamethasone. Proc Soc Exp Biol Med, 1999, 222(2): 185-193.
17. Wang X, Wang S, Zhou Y, et al. BM-MSCs protect against liver ischemia/reperfusion injury via HO-1 mediated autophagy. Mol Med Rep, 2018, 18(2): 2253-2262.
18. Hamedi-Asl P, Halabian R, Bahmani P, et al. Adenovirus-mediated expression of the HO-1 protein within MSCs decreased cytotoxicity and inhibited apoptosis induced by oxidative stresses. Cell Stress Chaperones, 2012, 17(2): 181-190.
19. Yu ZY, Ma D, He ZC, et al. Heme oxygenase-1 protects bone marrow mesenchymal stem cells from iron overload through decreasing reactive oxygen species and promoting IL-10 generation. Exp Cell Res, 2018, 362(1): 28-42.
20. Tang YL, Tang Y, Zhang YC, et al. Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. J Am Coll Cardiol, 2005, 46(7): 1339-1350.
21. Pan H, Guan D, Liu X, et al. SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Res, 2016, 26(2): 190-205.
22. Davis C, Dukes A, Drewry M, et al. MicroRNA-183-5p increases with age in bone-derived extracellular vesicles, suppresses bone marrow stromal (stem) cell proliferation, and induces stem cell senescence. Tissue Eng Part A, 2017, 23(21-22): 1231-1240.
23. Barbagallo I, Vanella A, Peterson SJ, et al. Overexpression of heme oxygenase-1 increases human osteoblast stem cell differentiation. J Bone Miner Metab, 2010, 28(3): 276-288.
24. Vanella L, Kim DH, Asprinio D, et al. HO-1 expression increases mesenchymal stem cell-derived osteoblasts but decreases adipocyte lineage. Bone, 2010, 46(1): 236-243.
25. Gu Q, Gu Y, Shi Q, et al. Hypoxia promotes osteogenesis of human placental-derived mesenchymal stem cells. Tohoku J Exp Med, 2016, 239(4): 287-296.
26. Liu X, Ji C, Xu L, et al. Hmox1 promotes osteogenic differentiation at the expense of reduced adipogenic differentiation induced by BMP9 in C3H10T1/2 cells. J Cell Biochem, 2018, 119(7): 5503-5516.
27. Shen ZY, Wu B, Liu T, et al. Immunomodulatory effects of bone marrow mesenchymal stem cells overexpressing heme oxygenase-1: Protective effects on acute rejection following reduced-size liver transplantation in a rat model. Cell Immunol, 2017, 313: 10-24.
28. Zhang D, Fu L, Wang L, et al. Therapeutic benefit of mesenchymal stem cells in pregnant rats with angiotensin receptor agonistic autoantibody-induced hypertension: Implications for immunomodulation and cytoprotection. Hypertens Pregnancy, 2017, 36(3): 247-258.
29. Suresh SC, Selvaraju V, Thirunavukkarasu M, et al. Thioredoxin-1(Trx1) engineered mesenchymal stem cell therapy increased pro-angiogenic factors, reduced fibrosis and improved heart function in the infarcted rat myocardium. Int J Cardiol, 2015, 201: 517-528.
30. Shu T, Zeng B, Ren X, et al. HO-1 modified mesenchymal stem cells modulate MMPs/TIMPs system and adverse remodeling in infarcted myocardium. Tissue Cell, 2010, 42(4): 217-222.
31. Wang J, Hu X, Jiang H. MSCs modified with HO-1 gene transplantation: A novel therapeutic approach for attenuating heart failure. Int J Cardiol, 2016, 214: 159-160.
32. Zhang ZH, Zhu W, Ren HZ, et al. Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure. Stem Cell Res Ther, 2017, 8(1): 70.
33. Chen X, Zhang Y, Wang W, et al. Mesenchymal stem cells modified with Heme oxygenase-1 have enhanced paracrine function and attenuate lipopolysaccharide-induced inflammatory and oxidative damage in pulmonary microvascular endothelial cells. Cell Physiol Biochem, 2018, 49(1): 101-122.
34. Liu N, Wang H, Han G, et al. Enhanced proliferation and differentiation of HO-1 gene-modified bone marrow-derived mesenchymal stem cells in the acute injured kidney. Int J Mol Med, 2018, 42(2): 946-956.
35. 王绕绕, 宋红丽. 自噬在肝移植缺血再灌注损伤中的研究进展. 中华器官移植杂志, 2015, 36(9): 565-568.
36. Wang Y, Wang JL, Ma HC, et al. Mesenchymal stem cells increase heme oxygenase 1-activated autophagy in treatment of acute liver failure. Biochem Biophys Res Commun, 2019, 508(3): 682-689.
37. Wang R, Shen Z, Yang L, et al. Protective effects of heme oxygenase-1-transduced bone marrow-derived mesenchymal stem cells on reduced-size liver transplantation: Role of autophagy regulated by the ERK/mTOR signaling pathway. Int J Mol Med, 2017, 40(5): 1537-1548.
38. Yu M, Wang J, Fang Q, et al. High expression of heme oxygenase-1 in target organs may attenuate acute graft-versus-host disease through regulation of immune balance of TH17/Treg. Transpl Immunol, 2016, 37: 10-17.
39. Lee HS, Song S, Shin DY, et al. Enhanced effect of human mesenchymal stem cells expressing human TNF-αR-Fc and HO-1 gene on porcine islet xenotransplantation in humanized mice. Xenotransplantation, 2018, 25(1). doi: 10.1111/xen.12342.
40. Wu B, Song HL, Yang Y, et al. Improvement of liver transplantation outcome by Heme oxygenase-1-transduced bone marrow mesenchymal stem cells in rats. Stem Cells Int, 2016, 2016: 9235073.
41. Yang L, Shen ZY, Wang RR, et al. Effects of heme oxygenase-1-modified bone marrow mesenchymal stem cells on microcirculation and energy metabolism following liver transplantation. World J Gastroenterol, 2017, 23(19): 3449-3467.
42. Yang Y, Song HL, Zhang W, et al. Heme oxygenase-1-transduced bone marrow mesenchymal stem cells in reducing acute rejection and improving small bowel transplantation outcomes in rats. Stem Cell Res Ther, 2016, 7(1): 164.
43. Yin ML, Song HL, Yang Y, et al. Effect of CXCR3/HO-1 genes modified bone marrow mesenchymal stem cells on small bowel transplant rejection. World J Gastroenterol, 2017, 23(22): 4016-4038.
44. Lee SH, Kim Y, Rhew D, et al. Effect of canine mesenchymal stromal cells overexpressing heme oxygenase-1 in spinal cord injury. J Vet Sci, 2017, 18(3): 377-386.
45. Hou C, Shen L, Huang Q, et al. The effect of heme oxygenase-1 complexed with collagen on MSC performance in the treatment of diabetic ischemic ulcer. Biomaterials, 2013, 34(1): 112-120.

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