Advancement of mesenchymal stem cells in relieving acute pancreatitis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

QU Yuanxu ¹ , DING Yixuan ¹ , ZHENG Zhi ¹ , LU Jiongdi ¹ ,  LI Fei ^1,2

1. Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, P. R. China;
2. Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing 100053, P. R. China;

Corresponding author：

LI Fei, Email: feili36@ccmu.edu.cn

Keywords：

acute pancreatitis; mesenchymal stem cell; therapy

DOI：

10.7507/1007-9424.202011100

Video：

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Objective To summarize the research progress of mesenchymal stem cells in acute pancreatitis animal models, and to explore the potential of mesenchymal stem cells in the treatment of acute pancreatitis.Method Wecollected domestic and foreign studies on mesenchymal stem cells in acute pancreatitis animal models and made a review.Results In the animal model of acute pancreatitis, the infusion of mesenchymal stem cells could reduce the expression of inflammatory factors, regulate the expression of immune cells, inhibit pancreatic cell apoptosis and autophagy, resist oxidative stress, and promote angiogenesis. Mesenchymal stem cells had a relieving effect on acute pancreatitis.Conclusion The infusion of mesenchymal stem cells can relieve acute pancreatitis in animal models, and has great potential in the clinical application of acute pancreatitis.

Citation： QU Yuanxu, DING Yixuan, ZHENG Zhi, LU Jiongdi, LI Fei. Advancement of mesenchymal stem cells in relieving acute pancreatitis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(10): 1365-1371. doi: 10.7507/1007-9424.202011100 Copy

1.	Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science, 1999, 284(5411): 143-147.
2.	Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol, 2008, 8(9): 726-736.
3.	Oh W, Kim DS, Yang YS, et al. Immunological properties of umbilical cord blood-derived mesenchymal stromal cells. Cell Immunol, 2008, 251(2): 116-123.
4.	Qin T, Liu CJ, Zhang HW, et al. Effect of the IkBα mutant gene delivery to mesenchymal stem cells on rat chronic pancreatitis. Genet Mol Res, 2014, 13(1): 371-385.
5.	Meier RP, Müller YD, Morel P, et al. Transplantation of mesenchymal stem cells for the treatment of liver diseases, is there enough evidence? Stem Cell Res, 2013, 11(3): 1348-1364.
6.	Zhang S, Chen L, Liu T, et al. Human umbilical cord matrix stem cells efficiently rescue acute liver failure through paracrine effects rather than hepatic differentiation. Tissue Eng Part A, 2012, 18(13-14): 1352-1364.
7.	Trounson A, McDonald C. Stem cell therapies in clinical trials: Progress and challenges. Cell Stem Cell, 2015, 17(1): 11-22.
8.	Xiao AY, Tan ML, Wu LM, et al. Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies. Lancet Gastroenterol Hepatol, 2016, 1(1): 45-55.
9.	Ahmed SM, Morsi M, Ghoneim NI, et al. Mesenchymal stromal cell therapy for pancreatitis: A systematic review. Oxid Med Cell Longev, 2018, 2018: 3250864.
10.	Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood, 2006, 107(1): 367-372.
11.	Abumaree MH, Abomaray FM, Alshabibi MA, et al. Immunomodulatory properties of human placental mesenchymal stem/stromal cells. Placenta, 2017, 59: 87-95.
12.	Parekkadan B, Milwid JM. Mesenchymal stem cells as therapeutics. Annu Rev Biomed Eng, 2010, 12: 87-117.
13.	Hu MS, Leavitt T, Malhotra S, et al. Stem cell-based therapeutics to improve wound healing. Plast Surg Int, 2015, 2015: 383581.
14.	Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet, 1970, 3(4): 393-403.
15.	Meng HB, Gong J, Zhou B, et al. Therapeutic effect of human umbilical cord-derived mesenchymal stem cells in rat severe acute pancreatitis. Int J Clin Exp Pathol, 2013, 6(12): 2703-2712.
16.	Qian D, Gong J, He Z, et al. Bone marrow-derived mesenchymal stem cells repair necrotic pancreatic tissue and promote angiogenesis by secreting cellular growth factors involved in the SDF-1 α/CXCR4 axis in rats. Stem Cells Int, 2015, 2015: 306836.
17.	Jung KH, Yi T, Son MK, et al. Therapeutic effect of human clonal bone marrow-derived mesenchymal stem cells in severe acute pancreatitis. Arch Pharm Res, 2015, 38(5): 742-751.
18.	Yin G, Hu G, Wan R, et al. Role of bone marrow mesenchymal stem cells in L-arg-induced acute pancreatitis: effects and possible mechanisms. Int J Clin Exp Pathol, 2015, 8(5): 4457-4468.
19.	Yin G, Hu G, Wan R, et al. Role of microvesicles from bone marrow mesenchymal stem cells in acute pancreatitis. Pancreas, 2016, 45(9): 1282-1293.
20.	Zhao H, He Z, Huang D, et al. Infusion of bone marrow mesenchymal stem cells attenuates experimental severe acute pancreatitis in rats. Stem Cells Int, 2016, 2016: 7174319.
21.	Kim HW, Song WJ, Li Q, et al. Canine adipose tissue-derived mesenchymal stem cells ameliorate severe acute pancreatitis by regulating T cells in rats. J Vet Sci, 2016, 17(4): 539-548.
22.	Qian D, Wei G, Xu C, et al. Bone marrow-derived mesenchymal stem cells (BMSCs) repair acute necrotized pancreatitis by secreting microRNA-9 to target the NF-κB1/p50 gene in rats. Sci Rep, 2017, 7(1): 581.
23.	Cai J, Zhou X, Yu H, et al. Effect of bone marrow mesenchymal stem cells on RhoA/ROCK signal pathway in severe acute pancreatitis. Am J Transl Res, 2019, 11(8): 4809-4816.
24.	Ma Z, Song G, Zhao D, et al. Bone marrow-derived mesenchymal stromal cells ameliorate severe acute pancreatitis in rats via hemeoxygenase-1-mediated anti-oxidant and anti-inflammatory effects. Cytotherapy, 2019, 21(2): 162-174.
25.	Dong H, Wang Z, Chen Y, et al. Protective effects of bone marrow-derived mesenchymal stem cells on insulin secretion and inflammation in the treatment of severe acute pancreatitis in rats. Transplant Proc, 2020, 52(1): 333-344.
26.	Wu Q, Wang F, Hou Y, et al. The effect of allogenetic bone marrow-derived mesenchymal stem cell transplantation on lung aquaporin-1 and -5 in a rat model of severe acute pancreatitis. Hepatogastroenterology, 2012, 59(116): 965-976.
27.	Lu F, Wang F, Chen Z, et al. Effect of mesenchymal stem cells on small intestinal injury in a rat model of acute necrotizing pancreatitis. Stem Cell Res Ther, 2017, 8(1): 12.
28.	Jung KH, Song SU, Yi T, et al. Human bone marrow-derived clonal mesenchymal stem cells inhibit inflammation and reduce acute pancreatitis in rats. Gastroenterology, 2011, 140(3): 998-1008.
29.	Qian D, Song G, Ma Z, et al. MicroRNA-9 modified bone marrow-derived mesenchymal stem cells (BMSCs) repair severe acute pancreatitis (SAP) via inducing angiogenesis in rats. Stem Cell Res Ther, 2018, 9(1): 282.
30.	Yang B, Bai B, Liu CX, et al. Effect of umbilical cord mesenchymal stem cells on treatment of severe acute pancreatitis in rats. Cytotherapy, 2013, 15(2): 154-162.
31.	Gong J, Meng HB, Hua J, et al. The SDF-1/CXCR4 axis regulates migration of transplanted bone marrow mesenchymal stem cells towards the pancreas in rats with acute pancreatitis. Mol Med Rep, 2014, 9(5): 1575-1582.
32.	He Z, Hua J, Qian D, et al. Intravenous hMSCs ameliorate acute pancreatitis in mice via secretion of tumor necrosis factor-α stimulated gene/protein 6. Sci Rep, 2016, 6: 38438.
33.	Li Q, Song WJ, Ryu MO, et al. TSG-6 secreted by human adipose tissue-derived mesenchymal stem cells ameliorates severe acute pancreatitis via ER stress downregulation in mice. Stem Cell Res Ther, 2018, 9(1): 255.
34.	Li HY, He HC, Song JF, et al. Bone marrow-derived mesenchymal stem cells repair severe acute pancreatitis by secreting miR-181a-5p to target PTEN/Akt/TGF-β1 signaling. Cell Signal, 2020, 66: 109436.
35.	Lin R, Li M, Luo M, et al. Mesenchymal stem cells decrease blood-brain barrier permeability in rats with severe acute pancreatitis. Cell Mol Biol Lett, 2019, 24: 43.
36.	Song G, Ma Z, Liu D, et al. Bone marrow-derived mesenchymal stem cells ameliorate severe acute pancreatitis by inhibiting necroptosis in rats. Mol Cell Biochem, 2019, 459(1-2): 7-19.
37.	Song G, Zhou J, Song R, et al. Long noncoding RNA H19 regulates the therapeutic efficacy of mesenchymal stem cells in rats with severe acute pancreatitis by sponging miR-138-5p and miR-141-3p. Stem Cell Res Ther, 2020, 11(1): 420.
38.	Chan YC, Leung PS. Acute pancreatitis: animal models and recent advances in basic research. Pancreas, 2007, 34(1): 1-14.
39.	Sweiry JH, Mann GE. Role of oxidative stress in the pathogenesis of acute pancreatitis. Scand J Gastroenterol Suppl, 1996, 219: 10-15.
40.	Krivoruchko IA, Gusak IV, Smachilo RM, et al. The role of the intestines in the pathogenesis of acute pancreatitis: oxygen extraction and bacteria translocation in rats. Klin Khir, 1999, (12): 40-42.
41.	Ma Z, Song G, Liu D, et al. N-Acetylcysteine enhances the therapeutic efficacy of bone marrow-derived mesenchymal stem cell transplantation in rats with severe acute pancreatitis. Pancreatology, 2019, 19(2): 258-265.
42.	Song G, Liu D, Geng X, et al. Bone marrow-derived mesenchymal stem cells alleviate severe acute pancreatitis-induced multiple-organ injury in rats via suppression of autophagy. Exp Cell Res, 2019, 385(2): 111674.
43.	Song G, Ma Z, Liu D, et al. Bone marrow-derived mesenchymal stem cells attenuate severe acute pancreatitis via regulation of microRNA-9 to inhibit necroptosis in rats. Life Sci, 2019, 223: 9-21.
44.	Liu D, Song G, Ma Z, et al. Resveratrol improves the therapeutic efficacy of bone marrow-derived mesenchymal stem cells in rats with severe acute pancreatitis. Int Immunopharmacol, 2020, 80: 106128.
45.	Yang J, Su J, Xi SS, et al. Human umbilical cord mesenchymal stem cells pretreated with angiotensin-Ⅱ attenuate pancreas injury of rats with severe acute pancreatitis. Biomed Pharmacother, 2019, 117: 109052.
46.	Hua J, He ZG, Qian DH, et al. Angiopoietin-1 gene-modified human mesenchymal stem cells promote angiogenesis and reduce acute pancreatitis in rats. Int J Clin Exp Pathol, 2014, 7(7): 3580-3595.
47.	Si YL, Zhao YL, Hao HJ, et al. MSCs: Biological characteristics, clinical applications and their outstanding concerns. Ageing Res Rev, 2011, 10(1): 93-103.
48.	Rozier P, Maria A, Goulabchand R, et al. Mesenchymal stem cells in systemic sclerosis: allogenic or autologous approaches for therapeutic use? Front Immunol, 2018, 9: 2938.
49.	Goodman RR, Jong MK, Davies JE. Concise review: The challenges and opportunities of employing mesenchymal stromal cells in the treatment of acute pancreatitis. Biotechnol Adv, 2020, 42: 107338.
50.	Eggenhofer E, Benseler V, Kroemer A, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol, 2012, 3: 297.
51.	Braid LR, Wood CA, Wiese DM, et al. Intramuscular administration potentiates extended dwell time of mesenchymal stromal cells compared to other routes. Cytotherapy, 2018, 20(2): 232-244.
52.	Wang Y, Han ZB, Song YP, et al. Safety of mesenchymal stem cells for clinical application. Stem Cells Int, 2012, 2012: 652034.
53.	Gong J, Zhang G, Tian F, et al. Islet-derived stem cells from adult rats participate in the repair of islet damage. J Mol Histol, 2012, 43(6): 745-750.
54.	Fang B, Song YP, Li N, et al. Resolution of refractory chronic autoimmune thrombocytopenic purpura following mesenchymal stem cell transplantation: a case report. Transplant Proc, 2009, 41(5): 1827-1830.
55.	Norman J. The role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg, 1998, 175(1): 76-83.

1. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science, 1999, 284(5411): 143-147.
2. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol, 2008, 8(9): 726-736.
3. Oh W, Kim DS, Yang YS, et al. Immunological properties of umbilical cord blood-derived mesenchymal stromal cells. Cell Immunol, 2008, 251(2): 116-123.
4. Qin T, Liu CJ, Zhang HW, et al. Effect of the IkBα mutant gene delivery to mesenchymal stem cells on rat chronic pancreatitis. Genet Mol Res, 2014, 13(1): 371-385.
5. Meier RP, Müller YD, Morel P, et al. Transplantation of mesenchymal stem cells for the treatment of liver diseases, is there enough evidence? Stem Cell Res, 2013, 11(3): 1348-1364.
6. Zhang S, Chen L, Liu T, et al. Human umbilical cord matrix stem cells efficiently rescue acute liver failure through paracrine effects rather than hepatic differentiation. Tissue Eng Part A, 2012, 18(13-14): 1352-1364.
7. Trounson A, McDonald C. Stem cell therapies in clinical trials: Progress and challenges. Cell Stem Cell, 2015, 17(1): 11-22.
8. Xiao AY, Tan ML, Wu LM, et al. Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies. Lancet Gastroenterol Hepatol, 2016, 1(1): 45-55.
9. Ahmed SM, Morsi M, Ghoneim NI, et al. Mesenchymal stromal cell therapy for pancreatitis: A systematic review. Oxid Med Cell Longev, 2018, 2018: 3250864.
10. Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood, 2006, 107(1): 367-372.
11. Abumaree MH, Abomaray FM, Alshabibi MA, et al. Immunomodulatory properties of human placental mesenchymal stem/stromal cells. Placenta, 2017, 59: 87-95.
12. Parekkadan B, Milwid JM. Mesenchymal stem cells as therapeutics. Annu Rev Biomed Eng, 2010, 12: 87-117.
13. Hu MS, Leavitt T, Malhotra S, et al. Stem cell-based therapeutics to improve wound healing. Plast Surg Int, 2015, 2015: 383581.
14. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet, 1970, 3(4): 393-403.
15. Meng HB, Gong J, Zhou B, et al. Therapeutic effect of human umbilical cord-derived mesenchymal stem cells in rat severe acute pancreatitis. Int J Clin Exp Pathol, 2013, 6(12): 2703-2712.
16. Qian D, Gong J, He Z, et al. Bone marrow-derived mesenchymal stem cells repair necrotic pancreatic tissue and promote angiogenesis by secreting cellular growth factors involved in the SDF-1 α/CXCR4 axis in rats. Stem Cells Int, 2015, 2015: 306836.
17. Jung KH, Yi T, Son MK, et al. Therapeutic effect of human clonal bone marrow-derived mesenchymal stem cells in severe acute pancreatitis. Arch Pharm Res, 2015, 38(5): 742-751.
18. Yin G, Hu G, Wan R, et al. Role of bone marrow mesenchymal stem cells in L-arg-induced acute pancreatitis: effects and possible mechanisms. Int J Clin Exp Pathol, 2015, 8(5): 4457-4468.
19. Yin G, Hu G, Wan R, et al. Role of microvesicles from bone marrow mesenchymal stem cells in acute pancreatitis. Pancreas, 2016, 45(9): 1282-1293.
20. Zhao H, He Z, Huang D, et al. Infusion of bone marrow mesenchymal stem cells attenuates experimental severe acute pancreatitis in rats. Stem Cells Int, 2016, 2016: 7174319.
21. Kim HW, Song WJ, Li Q, et al. Canine adipose tissue-derived mesenchymal stem cells ameliorate severe acute pancreatitis by regulating T cells in rats. J Vet Sci, 2016, 17(4): 539-548.
22. Qian D, Wei G, Xu C, et al. Bone marrow-derived mesenchymal stem cells (BMSCs) repair acute necrotized pancreatitis by secreting microRNA-9 to target the NF-κB1/p50 gene in rats. Sci Rep, 2017, 7(1): 581.
23. Cai J, Zhou X, Yu H, et al. Effect of bone marrow mesenchymal stem cells on RhoA/ROCK signal pathway in severe acute pancreatitis. Am J Transl Res, 2019, 11(8): 4809-4816.
24. Ma Z, Song G, Zhao D, et al. Bone marrow-derived mesenchymal stromal cells ameliorate severe acute pancreatitis in rats via hemeoxygenase-1-mediated anti-oxidant and anti-inflammatory effects. Cytotherapy, 2019, 21(2): 162-174.
25. Dong H, Wang Z, Chen Y, et al. Protective effects of bone marrow-derived mesenchymal stem cells on insulin secretion and inflammation in the treatment of severe acute pancreatitis in rats. Transplant Proc, 2020, 52(1): 333-344.
26. Wu Q, Wang F, Hou Y, et al. The effect of allogenetic bone marrow-derived mesenchymal stem cell transplantation on lung aquaporin-1 and -5 in a rat model of severe acute pancreatitis. Hepatogastroenterology, 2012, 59(116): 965-976.
27. Lu F, Wang F, Chen Z, et al. Effect of mesenchymal stem cells on small intestinal injury in a rat model of acute necrotizing pancreatitis. Stem Cell Res Ther, 2017, 8(1): 12.
28. Jung KH, Song SU, Yi T, et al. Human bone marrow-derived clonal mesenchymal stem cells inhibit inflammation and reduce acute pancreatitis in rats. Gastroenterology, 2011, 140(3): 998-1008.
29. Qian D, Song G, Ma Z, et al. MicroRNA-9 modified bone marrow-derived mesenchymal stem cells (BMSCs) repair severe acute pancreatitis (SAP) via inducing angiogenesis in rats. Stem Cell Res Ther, 2018, 9(1): 282.
30. Yang B, Bai B, Liu CX, et al. Effect of umbilical cord mesenchymal stem cells on treatment of severe acute pancreatitis in rats. Cytotherapy, 2013, 15(2): 154-162.
31. Gong J, Meng HB, Hua J, et al. The SDF-1/CXCR4 axis regulates migration of transplanted bone marrow mesenchymal stem cells towards the pancreas in rats with acute pancreatitis. Mol Med Rep, 2014, 9(5): 1575-1582.
32. He Z, Hua J, Qian D, et al. Intravenous hMSCs ameliorate acute pancreatitis in mice via secretion of tumor necrosis factor-α stimulated gene/protein 6. Sci Rep, 2016, 6: 38438.
33. Li Q, Song WJ, Ryu MO, et al. TSG-6 secreted by human adipose tissue-derived mesenchymal stem cells ameliorates severe acute pancreatitis via ER stress downregulation in mice. Stem Cell Res Ther, 2018, 9(1): 255.
34. Li HY, He HC, Song JF, et al. Bone marrow-derived mesenchymal stem cells repair severe acute pancreatitis by secreting miR-181a-5p to target PTEN/Akt/TGF-β1 signaling. Cell Signal, 2020, 66: 109436.
35. Lin R, Li M, Luo M, et al. Mesenchymal stem cells decrease blood-brain barrier permeability in rats with severe acute pancreatitis. Cell Mol Biol Lett, 2019, 24: 43.
36. Song G, Ma Z, Liu D, et al. Bone marrow-derived mesenchymal stem cells ameliorate severe acute pancreatitis by inhibiting necroptosis in rats. Mol Cell Biochem, 2019, 459(1-2): 7-19.
37. Song G, Zhou J, Song R, et al. Long noncoding RNA H19 regulates the therapeutic efficacy of mesenchymal stem cells in rats with severe acute pancreatitis by sponging miR-138-5p and miR-141-3p. Stem Cell Res Ther, 2020, 11(1): 420.
38. Chan YC, Leung PS. Acute pancreatitis: animal models and recent advances in basic research. Pancreas, 2007, 34(1): 1-14.
39. Sweiry JH, Mann GE. Role of oxidative stress in the pathogenesis of acute pancreatitis. Scand J Gastroenterol Suppl, 1996, 219: 10-15.
40. Krivoruchko IA, Gusak IV, Smachilo RM, et al. The role of the intestines in the pathogenesis of acute pancreatitis: oxygen extraction and bacteria translocation in rats. Klin Khir, 1999, (12): 40-42.
41. Ma Z, Song G, Liu D, et al. N-Acetylcysteine enhances the therapeutic efficacy of bone marrow-derived mesenchymal stem cell transplantation in rats with severe acute pancreatitis. Pancreatology, 2019, 19(2): 258-265.
42. Song G, Liu D, Geng X, et al. Bone marrow-derived mesenchymal stem cells alleviate severe acute pancreatitis-induced multiple-organ injury in rats via suppression of autophagy. Exp Cell Res, 2019, 385(2): 111674.
43. Song G, Ma Z, Liu D, et al. Bone marrow-derived mesenchymal stem cells attenuate severe acute pancreatitis via regulation of microRNA-9 to inhibit necroptosis in rats. Life Sci, 2019, 223: 9-21.
44. Liu D, Song G, Ma Z, et al. Resveratrol improves the therapeutic efficacy of bone marrow-derived mesenchymal stem cells in rats with severe acute pancreatitis. Int Immunopharmacol, 2020, 80: 106128.
45. Yang J, Su J, Xi SS, et al. Human umbilical cord mesenchymal stem cells pretreated with angiotensin-Ⅱ attenuate pancreas injury of rats with severe acute pancreatitis. Biomed Pharmacother, 2019, 117: 109052.
46. Hua J, He ZG, Qian DH, et al. Angiopoietin-1 gene-modified human mesenchymal stem cells promote angiogenesis and reduce acute pancreatitis in rats. Int J Clin Exp Pathol, 2014, 7(7): 3580-3595.
47. Si YL, Zhao YL, Hao HJ, et al. MSCs: Biological characteristics, clinical applications and their outstanding concerns. Ageing Res Rev, 2011, 10(1): 93-103.
48. Rozier P, Maria A, Goulabchand R, et al. Mesenchymal stem cells in systemic sclerosis: allogenic or autologous approaches for therapeutic use? Front Immunol, 2018, 9: 2938.
49. Goodman RR, Jong MK, Davies JE. Concise review: The challenges and opportunities of employing mesenchymal stromal cells in the treatment of acute pancreatitis. Biotechnol Adv, 2020, 42: 107338.
50. Eggenhofer E, Benseler V, Kroemer A, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol, 2012, 3: 297.
51. Braid LR, Wood CA, Wiese DM, et al. Intramuscular administration potentiates extended dwell time of mesenchymal stromal cells compared to other routes. Cytotherapy, 2018, 20(2): 232-244.
52. Wang Y, Han ZB, Song YP, et al. Safety of mesenchymal stem cells for clinical application. Stem Cells Int, 2012, 2012: 652034.
53. Gong J, Zhang G, Tian F, et al. Islet-derived stem cells from adult rats participate in the repair of islet damage. J Mol Histol, 2012, 43(6): 745-750.
54. Fang B, Song YP, Li N, et al. Resolution of refractory chronic autoimmune thrombocytopenic purpura following mesenchymal stem cell transplantation: a case report. Transplant Proc, 2009, 41(5): 1827-1830.
55. Norman J. The role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg, 1998, 175(1): 76-83.

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