Skip to main content
Top
Published in: European Journal of Trauma and Emergency Surgery 1/2020

01-02-2020 | Polytrauma | Original Article

Mesenchymal stem cell transplantation in polytrauma: Evaluation of bone and liver healing response in an experimental rat model

Authors: Ayça Koca Tanrıverdi, Onur Polat, Ayşe Eser Elçin, Ozan Ahlat, Günhan Gürman, Müge Günalp, Ahmet Burak Oğuz, Sinan Genç, Yaşar Murat Elçin

Published in: European Journal of Trauma and Emergency Surgery | Issue 1/2020

Login to get access

Abstract

Purpose

Trauma is the most common cause of death of young people in the world. As known, mesenchymal stem cells (MSCs) accelerate tissue regeneration mechanisms. In our study, we aimed to investigate the effects of MSCs transplantation on the healing of liver and bone tissue by considering trauma secondary inflammatory responses.

Methods

56 adult Wistar-albino rats were divided into two groups: the polytrauma (liver and bone) (n = 28), and the liver trauma group (n = 28). At 36 h and 5th day after surgery, both rats with polytrauma and with isolated liver injury received either intravenous (IV) or intraperitoneal (IP) injections of MSCs (one million cells per kg body weight). Untreated groups received IV and IP saline injections. At day 21 after surgery, liver, tibia and fibula of the subjects were excised and evaluated for histopathologic and histomorphometric examination. Additionally, whole blood count (white blood cells, hemoglobin and platelets), C-reactive protein (CRP), glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, blood gas, and trauma markers interleukin-1B (IL-1B), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF alpha) levels were investigated.

Results

In general, MSC transplantations were well tolerated by the subjects. It was found that ALT, CRP, albumin were significantly lower in rats which received MSCs (p < 0.001). Inflammation of the liver and bone tissue in the MSC-injected rats were significantly lower than that of the untreated groups.

Conclusions

Herewith we have shown that MSC infusion in posttraumatic rats leads to less aggressive and more effective consequences on liver and bone tissue healing. Human MSC treatment for trauma is still in early stages of development; thus standard protocols, and patient inclusion criteria should be established beforehand clinical trials.
Appendix
Available only for authorised users
Literature
1.
go back to reference Peden M, McGee K, Sharma G. The injury chart book: a graphical overview of the global burden of injuries. Geneva, World Health Organization, 2002. Peden M, McGee K, Sharma G. The injury chart book: a graphical overview of the global burden of injuries. Geneva, World Health Organization, 2002.
2.
go back to reference Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell. 2015;17:11–22.PubMed Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell. 2015;17:11–22.PubMed
3.
go back to reference Çelebi B, Elçin AE, Elçin YM. Proteome analysis of rat bone marrow mesenchymal stem cell differentiation. J Proteome Res. 2010;9(10):5217–27.CrossRefPubMed Çelebi B, Elçin AE, Elçin YM. Proteome analysis of rat bone marrow mesenchymal stem cell differentiation. J Proteome Res. 2010;9(10):5217–27.CrossRefPubMed
4.
go back to reference Baykan E, Koc A, Elçin AE, Elçin YM. Evaluation of a biomimetic poly(ε-caprolactone)/β-tricalcium phosphate multispiral scaffold for bone tissue engineering: in vitro and in vivo studies. Biointerphases. 2014;9:029011.CrossRefPubMed Baykan E, Koc A, Elçin AE, Elçin YM. Evaluation of a biomimetic poly(ε-caprolactone)/β-tricalcium phosphate multispiral scaffold for bone tissue engineering: in vitro and in vivo studies. Biointerphases. 2014;9:029011.CrossRefPubMed
5.
go back to reference Emin N, Koç A, Durkut S, Elçin AE, Elçin YM. Engineering of rat articular cartilage on porous sponges: Effects of TGF-beta 1 and microgravity bioreactor culture. Artif Cell Blood Sub. 2008;36(2):123–37.CrossRef Emin N, Koç A, Durkut S, Elçin AE, Elçin YM. Engineering of rat articular cartilage on porous sponges: Effects of TGF-beta 1 and microgravity bioreactor culture. Artif Cell Blood Sub. 2008;36(2):123–37.CrossRef
6.
go back to reference Beşaltı Ö, Aktaş Z, Can P, Akpınar E, Elçin AE, Elçin YM. The use of autologous neurogenically-induced bone marrow-derived mesenchymal stem cells for the treatment of paraplegic dogs without nociception due to spinal trauma. J Vet Med Sci. 2016;78(9):1465–73.CrossRefPubMedPubMedCentral Beşaltı Ö, Aktaş Z, Can P, Akpınar E, Elçin AE, Elçin YM. The use of autologous neurogenically-induced bone marrow-derived mesenchymal stem cells for the treatment of paraplegic dogs without nociception due to spinal trauma. J Vet Med Sci. 2016;78(9):1465–73.CrossRefPubMedPubMedCentral
7.
go back to reference Sikand M, Williams K, White C, Moran CG. The financial cost of treating polytrauma: implications for tertiary referral centres in the United Kingdom. Injury. 2005;36(6):733–7.CrossRefPubMed Sikand M, Williams K, White C, Moran CG. The financial cost of treating polytrauma: implications for tertiary referral centres in the United Kingdom. Injury. 2005;36(6):733–7.CrossRefPubMed
8.
go back to reference Hoffmann J, Glassford AJ, Doyle TC, Robbins RC, Schrepfer S, Pelletier MP. Angiogenic effects despite limited cell survival of bone marrow-derived mesenchymal stem cells under ischemia. Thorac Cardiov Surg. 2010;58(3):136–42.CrossRef Hoffmann J, Glassford AJ, Doyle TC, Robbins RC, Schrepfer S, Pelletier MP. Angiogenic effects despite limited cell survival of bone marrow-derived mesenchymal stem cells under ischemia. Thorac Cardiov Surg. 2010;58(3):136–42.CrossRef
9.
go back to reference Plaschke K. Human adult mesenchymal stem cells improve rat spatial cognitive function after systemic hemorrhagic shock. Behav Brain Res. 2009;201(2):332–7.CrossRefPubMed Plaschke K. Human adult mesenchymal stem cells improve rat spatial cognitive function after systemic hemorrhagic shock. Behav Brain Res. 2009;201(2):332–7.CrossRefPubMed
10.
go back to reference Abdollahi H, Harris LJ, Zhang P, McIlhenny S, Srinivas V, Tulenko T, DiMuzio PJ. The role of hypoxia in stem cell differentiation and therapeutics. J Surg Res. 2011;165(1):112–7.CrossRefPubMed Abdollahi H, Harris LJ, Zhang P, McIlhenny S, Srinivas V, Tulenko T, DiMuzio PJ. The role of hypoxia in stem cell differentiation and therapeutics. J Surg Res. 2011;165(1):112–7.CrossRefPubMed
12.
go back to reference Kim PK, Deutschman CS. Inflammatory responses and mediators. Surg Clin North Am. 2000;80(3):885–94.CrossRefPubMed Kim PK, Deutschman CS. Inflammatory responses and mediators. Surg Clin North Am. 2000;80(3):885–94.CrossRefPubMed
15.
go back to reference Çelebi B, Elçin YM. Proteome analysis of rat bone marrow mesenchymal stem cell subcultures. J Proteome Res. 2009;8(5):2164–72.CrossRefPubMed Çelebi B, Elçin YM. Proteome analysis of rat bone marrow mesenchymal stem cell subcultures. J Proteome Res. 2009;8(5):2164–72.CrossRefPubMed
16.
go back to reference Odabas S, Elçin AE, Elçin YM. Isolation and characterization of mesenchymal stem cells. Methods Mol Biol. 2014;1109:47–63.CrossRefPubMed Odabas S, Elçin AE, Elçin YM. Isolation and characterization of mesenchymal stem cells. Methods Mol Biol. 2014;1109:47–63.CrossRefPubMed
17.
go back to reference Conover WJ. Chapter 5-Some methods based on ranks, Sect. 5.2 Several independent samples. Multiple comparison test. In: Conower WJ, editor. Practical Nonparametric Statistics. 2nd ed. New York: Wiley; 1980. pp. 229–39. Conover WJ. Chapter 5-Some methods based on ranks, Sect. 5.2 Several independent samples. Multiple comparison test. In: Conower WJ, editor. Practical Nonparametric Statistics. 2nd ed. New York: Wiley; 1980. pp. 229–39.
18.
go back to reference Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A. Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy. 2006;8(4):315–7.CrossRefPubMed Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A. Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy. 2006;8(4):315–7.CrossRefPubMed
19.
go back to reference Cox JM, Kalns JE. Development and characterization of a rat model of nonpenetrating liver trauma. Comp Med. 2010;60(3):218–24.PubMedPubMedCentral Cox JM, Kalns JE. Development and characterization of a rat model of nonpenetrating liver trauma. Comp Med. 2010;60(3):218–24.PubMedPubMedCentral
20.
go back to reference Scalea TM, Boswell SA, Baron BJ, Ma OJ. Chapter 260. Abdominal trauma. In: Tintinalli JE, editor. Tintinalli’s emergency medicine: a comprehensive study guide. New York: McGraw-Hill; 2013. pp. 1765–70. Scalea TM, Boswell SA, Baron BJ, Ma OJ. Chapter 260. Abdominal trauma. In: Tintinalli JE, editor. Tintinalli’s emergency medicine: a comprehensive study guide. New York: McGraw-Hill; 2013. pp. 1765–70.
21.
go back to reference Sun L, Fan X, Zhang L, Shi G, Aili M, Lu X, Jiang T, Zhang Y. Bone mesenchymal stem cell transplantation via four routes for the treatment of acute liver failure in rats. Int J Mol Med. 2014;34(4):987–96.CrossRefPubMedPubMedCentral Sun L, Fan X, Zhang L, Shi G, Aili M, Lu X, Jiang T, Zhang Y. Bone mesenchymal stem cell transplantation via four routes for the treatment of acute liver failure in rats. Int J Mol Med. 2014;34(4):987–96.CrossRefPubMedPubMedCentral
22.
go back to reference Nathwani RA, Pais S, Reynolds TB, Kaplowitz N. Serum alanine aminotransferase in skeletal muscle diseases. Hepatology. 2005;41:380–2.CrossRefPubMed Nathwani RA, Pais S, Reynolds TB, Kaplowitz N. Serum alanine aminotransferase in skeletal muscle diseases. Hepatology. 2005;41:380–2.CrossRefPubMed
23.
go back to reference Kurtz DM, Travlos GS. The clinical chemistry of laboratory animals. 3rd ed. CRC Press; 2017. Kurtz DM, Travlos GS. The clinical chemistry of laboratory animals. 3rd ed. CRC Press; 2017.
24.
go back to reference Kaplan LJ, Frangos S. Clinical review: Acid-base abnormalities in the intensive care unit—Part II. Crit Care. 2005;9(2):198–203.CrossRefPubMed Kaplan LJ, Frangos S. Clinical review: Acid-base abnormalities in the intensive care unit—Part II. Crit Care. 2005;9(2):198–203.CrossRefPubMed
25.
go back to reference Jeng JC, Jablonski K, Bridgeman A, Jordan MH. Serum lactate, not base deficit, rapidly predicts survival after major burns. Burns. 2002;28(2):161–6.CrossRefPubMed Jeng JC, Jablonski K, Bridgeman A, Jordan MH. Serum lactate, not base deficit, rapidly predicts survival after major burns. Burns. 2002;28(2):161–6.CrossRefPubMed
26.
go back to reference Krumina G, Babarykin D, Krumina Z, Paegle I, Suhorukov O, Vanags D, Makarenkova G, Nikulshin S, Folkmane I. Effects of systemically transplanted allogeneic bone marrow multipotent mesenchymal stromal cells on rats’ recovery after experimental polytrauma. J Trauma Acute Care Surg. 2013;74(3):785–91.CrossRefPubMed Krumina G, Babarykin D, Krumina Z, Paegle I, Suhorukov O, Vanags D, Makarenkova G, Nikulshin S, Folkmane I. Effects of systemically transplanted allogeneic bone marrow multipotent mesenchymal stromal cells on rats’ recovery after experimental polytrauma. J Trauma Acute Care Surg. 2013;74(3):785–91.CrossRefPubMed
27.
go back to reference Babarikins D, Krumina G, Paegle I, Amerika D, Krūmiņa Z, Vanags D, Tihomirova T. Allogeneic bone marrow multipotent mesenchymal stromal cells and polytrauma repair: the role of fractionated on the basis of molecular mass red beetroot juice in the prevention of transplanted cells side effects in rats. Proc Latvian Acad Sci. 2013;67(1):52–60. Babarikins D, Krumina G, Paegle I, Amerika D, Krūmiņa Z, Vanags D, Tihomirova T. Allogeneic bone marrow multipotent mesenchymal stromal cells and polytrauma repair: the role of fractionated on the basis of molecular mass red beetroot juice in the prevention of transplanted cells side effects in rats. Proc Latvian Acad Sci. 2013;67(1):52–60.
28.
go back to reference Goldwasser P, Feldman J. Association of serum albumin and mortality risk. J Clin Epidemiol. 1997;50(6):693–703.CrossRefPubMed Goldwasser P, Feldman J. Association of serum albumin and mortality risk. J Clin Epidemiol. 1997;50(6):693–703.CrossRefPubMed
29.
go back to reference Yilmaz E, Bor C, Uyar M, Demirag K, Cankayali I. The effect of lactate, albumin, C-reactive protein, PaO2/FiO2 and glucose levels of trauma patients at the time of administration to intensive care unit on mortality. Turk J Intense Care. 2014;12:82–5. Yilmaz E, Bor C, Uyar M, Demirag K, Cankayali I. The effect of lactate, albumin, C-reactive protein, PaO2/FiO2 and glucose levels of trauma patients at the time of administration to intensive care unit on mortality. Turk J Intense Care. 2014;12:82–5.
30.
go back to reference Fröhlich M, Hildebrand F, Weuster M, Mommsen P, Mohr J, Witte I, Raeven P, Ruchholtz S, Flohé S, van Griensven M, Pape HC, Pfeifer R. Induced hypothermia reduces the hepatic inflammatory response in a swine multiple trauma model. J Trauma Acute Care Surg. 2014;76(6):1425–32.CrossRefPubMed Fröhlich M, Hildebrand F, Weuster M, Mommsen P, Mohr J, Witte I, Raeven P, Ruchholtz S, Flohé S, van Griensven M, Pape HC, Pfeifer R. Induced hypothermia reduces the hepatic inflammatory response in a swine multiple trauma model. J Trauma Acute Care Surg. 2014;76(6):1425–32.CrossRefPubMed
31.
go back to reference Voss JO, Loebel C, Bara JJ, Fussinger MA, Duttenhoefer F, Alini M, Stoddart MJ. Effect of short-term stimulation with interleukin-1beta and differentiation medium on human mesenchymal stromal cell paracrine activity in coculture with osteoblasts. Biomed Res Int. 2015; 714230. Voss JO, Loebel C, Bara JJ, Fussinger MA, Duttenhoefer F, Alini M, Stoddart MJ. Effect of short-term stimulation with interleukin-1beta and differentiation medium on human mesenchymal stromal cell paracrine activity in coculture with osteoblasts. Biomed Res Int. 2015; 714230.
32.
go back to reference Lange J, Sapozhnikova A, Lu C, Hu D, Li X, Miclau T, Marcucio RS. Action of IL-1beta during fracture healing. J Orthop Res. 2010;28(6):778–84.PubMedPubMedCentral Lange J, Sapozhnikova A, Lu C, Hu D, Li X, Miclau T, Marcucio RS. Action of IL-1beta during fracture healing. J Orthop Res. 2010;28(6):778–84.PubMedPubMedCentral
33.
go back to reference Kamiya A, Inagaki Y. Stem and progenitor cell systems in liver development and regeneration. Hepatol Res. 2015;45(1):29–37.CrossRefPubMed Kamiya A, Inagaki Y. Stem and progenitor cell systems in liver development and regeneration. Hepatol Res. 2015;45(1):29–37.CrossRefPubMed
34.
go back to reference Gruttadauria S, Grosso G, Pagano D, Biondi A, Echeverri GJ, Seria E, Pietrosi G, Liotta R, Basile F, Gridelli B. Marrow-derived mesenchymal stem cells restore biochemical markers of acute liver injury in experimental model. Transplant Proc. 2013; 45(2):480–486.CrossRefPubMed Gruttadauria S, Grosso G, Pagano D, Biondi A, Echeverri GJ, Seria E, Pietrosi G, Liotta R, Basile F, Gridelli B. Marrow-derived mesenchymal stem cells restore biochemical markers of acute liver injury in experimental model. Transplant Proc. 2013; 45(2):480–486.CrossRefPubMed
35.
go back to reference Carvalho AB, Quintanilha LF, Dias JV, Paredes BD, Mannheimer EG, Carvalho FG, Asensi KD, Gutfilen B, Fonseca LM, Resende CM, Rezende GF, Takiya CM, de Carvalho AC, Goldenberg RC. Bone marrow multipotent mesenchymal stromal cells do not reduce fibrosis or improve function in a rat model of severe chronic liver injury. Stem Cells. 2008;26(5):1307–14.CrossRefPubMed Carvalho AB, Quintanilha LF, Dias JV, Paredes BD, Mannheimer EG, Carvalho FG, Asensi KD, Gutfilen B, Fonseca LM, Resende CM, Rezende GF, Takiya CM, de Carvalho AC, Goldenberg RC. Bone marrow multipotent mesenchymal stromal cells do not reduce fibrosis or improve function in a rat model of severe chronic liver injury. Stem Cells. 2008;26(5):1307–14.CrossRefPubMed
36.
go back to reference Polat O, Polat G, Karahuseyinoglu S, Kutlay NY, Tasci AG, Erdemli E, Tukun A, Avunduk MC, Küplülü S, Demirtas M. Bone fracture healing with umbilico-placental mononuclear cells: a controlled animal study. Eur J Trauma Emerg Surg. 2010;36(1):60–6.CrossRefPubMed Polat O, Polat G, Karahuseyinoglu S, Kutlay NY, Tasci AG, Erdemli E, Tukun A, Avunduk MC, Küplülü S, Demirtas M. Bone fracture healing with umbilico-placental mononuclear cells: a controlled animal study. Eur J Trauma Emerg Surg. 2010;36(1):60–6.CrossRefPubMed
37.
go back to reference Wiegner R, Rudhart NE, Barth E, Gebhard F, Lampl L, Huber-Lang MS, Brenner RE. Mesenchymal stem cells in peripheral blood of severely injured patients. Eur J Trauma Emerg Surg. 2018;44(4):627–36.CrossRefPubMed Wiegner R, Rudhart NE, Barth E, Gebhard F, Lampl L, Huber-Lang MS, Brenner RE. Mesenchymal stem cells in peripheral blood of severely injured patients. Eur J Trauma Emerg Surg. 2018;44(4):627–36.CrossRefPubMed
Metadata
Title
Mesenchymal stem cell transplantation in polytrauma: Evaluation of bone and liver healing response in an experimental rat model
Authors
Ayça Koca Tanrıverdi
Onur Polat
Ayşe Eser Elçin
Ozan Ahlat
Günhan Gürman
Müge Günalp
Ahmet Burak Oğuz
Sinan Genç
Yaşar Murat Elçin
Publication date
01-02-2020
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Trauma and Emergency Surgery / Issue 1/2020
Print ISSN: 1863-9933
Electronic ISSN: 1863-9941
DOI
https://doi.org/10.1007/s00068-019-01101-9

Other articles of this Issue 1/2020

European Journal of Trauma and Emergency Surgery 1/2020 Go to the issue