Cell therapy, known in the media and among laypeople as stem cell treatment, has been under debate on several totally different fronts. The main confusion, which still persists even though it has been about for many years, is related to the use of embryonic stem cells in experimental and pre-clinical studies; today this occurs in most countries(11. Xia G, Santostefano KE, Goodwin M, Liu J, Subramony SH, Swanson MS, et al. Generation of neural cells from DM1 induced pluripotent stem cells as cellular model for the study of central nervous system neuropathogenesis. Cell Reprogram. 2013;15(2):166-77.,22. Zhang Y, Liao S, Yang M, Liang X, Poon MW, Wong CY, et al. Improved cell survival and paracrine capacity of human embryonic stem cell-derived mesenchymal stem cells promote therapeutic potential for pulmonary arterial hypertension. Cell Transplant. 2012;21(10):2225-39.) but great difficulties exist in Brazil until now(33. McMahon DS, Singer PA, Daar AS, Thorsteinsdóttir H. Regenerative medicine in Brazil: small but innovative. Regen Med. 2010;5(6):863-76.). This issue was debated extensively for four years in the Brazilian society and in 2008 the Supreme Court legalized studies using human embryonic stem cells. Subsequently, this measure allowed the first line of human embryonic stem cells to be obtained in Brazil(44. Fraga AM, Sukoyan M, Rajan P, Braga DP, Iaconelli A Jr, Franco JG Jr, et al. Establishment of a Brazilian line of human embryonic stem cells in defined medium: implications for cell therapy in an ethnically diverse population. Cell Transplant. 2011;20(3):431-40.). Notwithstanding the controversial source of the embryo, in its strict sense cell therapy is a medical procedure that is not new as it goes back centuries to the time when human and even animal blood first began to be used for therapeutic purposes. Landsteiner's discovery of the ABO blood group system in 1900, complemented by the Rh blood group system, paved the way for the incorporation of transfusion medicine in the medical practice(55. Landsteiner K, Levine P. On individual differences in human blood. J Exp Med. 1928;47(5):757-75.). Cell replacement therapy using red blood cells and blood components enabled the treatment of many diseases and allowed a leap in surgical techniques including solid organ transplants.
The fear of nuclear war and its foreseeable immediate and long-term consequences on human
beings helped the progression of research which aimed to minimize the effects with the
evolution of reparative cell therapy using bone marrow transplants, which are now called
hematopoietic stem cell transplantation (HSCT). This procedure is today common practice.
Hereditary and acquired hematologic diseases including onco-hematology, autoimmune and
immunodeficiency diseases are on the list of indications for HSCT with this list still
expanding(66. Voltarelli JC, Ortega ET, Pasquini R. Transplante de células tronco
hematopoéticas. São Paulo; Atheneu: 2009.). At the start
of this millennium, the studies and results of cell therapy in degenerative and chronic
diseases, the emergence of the concepts of cellular plasticity(77. Roy S, Gascard P, Dumont N, Zhao J, Pan D, Petrie S, et al. Rare
somatic cells from human breast tissue exhibit extensive lineage plasticity. Proc
Natl Acad Sci USA. 2013;110(12):4598-603.
8. Fuhrmann S, Zou C, Levine EM. Retinal pigment epithelium development,
plasticity, and tissue homeostasis. Exp Eye Res. 2013 Sep 21. [Epub ahead of
print]-99. Kim HA, Mindos T, Parkinson DB. Plastic fantastic: Schwann cells and
repair of the peripheral nervous system. Stem Cells Transl Med.
2013;2(8):553-7.), transdifferentiation and fusion(1010. Knapp D, Tanaka EM. Regeneration and reprogramming. Curr Opin Genet
Dev. 2012;22(5):485-93.
11. Ma T, Xie M, Laurent T, Ding S. Progress in the reprogramming of
somatic cells. Circ Res. 2013;112(3):562-74.-1212. Wilkinson AC, Göttgens B. Transcriptional regulation of
haematopoietic stem cells. Adv Exp Med Biol. 2013;786:187-212.),
and the description of the paracrine effect of cells(1313. Kishore R, Verma SK, Mackie AR, Vaughan EE, Abramova TV, Aiko I, et
al. Bone marrow progenitor cell therapy-mediated paracrine regulation of cardiac
miRNA-155 modulates fibrotic response in diabetic hearts. PLoS One.
2013;8(4):e60161.), opened new perspectives for research in regenerative
therapy using different sources of cells including the bone marrow, peripheral blood and
umbilical cord blood. So began the era of regenerative cell therapy, a movement that has
caught the imagination of the scientific, academic and lay communities with the idea of new
approaches to treat incurable diseases and common diseases that lack good therapeutic
options(1414. Ruiz MA. A era da terapia celular. Rev Bras Hematol Hemoter.
2005;27(1):4.). Auspicious
results have been described using several experimental models including in myocardial
infarction after the use of cell therapy in a small sample of patients(1515. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et
al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410(6829):701-5.
Comment in: Nature. 2004;428(6983):607-8; Nature. 2004;428(6983):587; Nature. 2001;
410(6829):640-1.). The number of publications on the use
of stem cells has been expanding geometrically and so publications in all areas of medicine
are becoming commonplace.
The same has occurred in respect to heart disease in Brazil and after the publication of promising results in Chagasic cardiomyopathy(1616. Soares MB, Garcia S, Campos de Carvalho AC, Ribeiro dos Santos R. Cellular therapy in Chagas' disease: potential applications in patients with chronic cardiomyopathy. Regen Med. 2007;2(3):257-64.), a large double-blind, randomized clinical trial was designed involving 1200 patients with diverse heart diseases(1717. Tura BR, Martino HF, Gowdak LH, dos Santos RR, Dohmann HF, Krieger JE, et al. Multicenter randomized trial of cell therapy in cardiopathies - MiHeart Study. Trials. 2007;8:2.,1818. Dohmann HF, Silva SA, Sousa AL, Braga AM, Branco RV, Haddad AF, et al. Multicenter double blind trial of autologous bone marrow mononuclear cell transplantation through intracoronary injection post acute myocardium infarction - MiHeart/AMI study. Trials. 2008;9:41.).
Subsequently, after 2005 government resources are being allocated to research projects; the National Network of Cell Therapy was created resulting in the establishment of several cell therapy Centers (Figure 1)(1919. Mendez-Otero R, Campos de Carvalho AC. Global update: Brazil. Regen Med. 2012;7(6 Suppl):144-7.). Investment by the Brazilian Government in the area of cell therapy is shown in Table 1.
Number of new cell therapy centers by state established after the creation of the National Network of Cell Therapy. Adapted from Mendez-Otero et al.(1919. Mendez-Otero R, Campos de Carvalho AC. Global update: Brazil. Regen Med. 2012;7(6 Suppl):144-7.)
BA: Bahia; RJ: Rio de Janeiro; SP: São Paulo; PR: Paraná; RS: Rio Grande do Sul
Despite these advances, several questions remain unanswered and the pressure of the
community continues in light of the positive results that have been observed in different
diseases(2020. Schoenfeld M, Frishman WH, Leri A, Kajstura J, Anversa P. The
existence of myocardial repair: mechanistic insights and enhancements. Cardiol Rev.
2013;21(3):111-20.
21. Yamaguchi T, Kanayasu-Toyoda T, Uchida E. Angiogenic cell therapy
for severe ischemic diseases. Biol Pharm Bull. 2013;36(2):176-81.
22. Diniz B, Thomas P, Thomas B, Ribeiro R, Hu Y, Brant R, et al.
Subretinal implantation of retinal pigment epithelial cells derived from human
embryonic stem cells: improved survival when implanted as a monolayer. Invest
Ophthalmol Vis Sci. 2013;54(7):5087-96.
23. Benoit E, O'Donnell TF, Patel AN. Safety and efficacy of autologous
cell therapy in critical limb ischemia: a systematic review. Cell Transplant.
2013;22(3):545-62.
24. Benoit E, O'Donnell TF Jr, Kitsios GD, Iafrati MD. Improved
amputation-free survival in unreconstructable critical limb ischemia and its
implications for clinical trial design and quality measurement. J Vasc Surg.
2012;55(3):781-9.-2525. Anversa P, Kajstura J, Rota M, Leri A. Regenerating new heart with
stem cells. J Clin Invest. 2013;123(1):62-70.). These results do not go unnoticed in
the electronic communication age; they quickly become common knowledge. This issue was
reviewed and discussed in presentations on the theme during the congress of the
Sociedade Brasileira de Transplante de Medula Óssea recently held in
São Paulo. Among the topics presented, the potential of using mesenchymal stem cells (MST)
was debated with their possible use in patients with graft-versus-host disease (GVHD) being
stressed. This common adverse reaction after allogeneic HSCT is frequently difficult to
control and so the use of MST is indicated in these situations. In Brazil the use of MST is
restricted to patients enrolled in clinical trials, which makes it difficult for centers
around the country, that are both competent and technically prepared, to offer this type of
therapy to a larger number of patients(2626. de Santis GC, Ubiali EM, Covas DT. Compassionate use of cell
products. Rev Bras Hematol Hemoter. 2013;35(2):144-5.). The compassionate use of MST in these cases, when necessary, is
based on the data available in the medical literature. This topic has been discussed by
Medical and Research Ethics Committees with great repercussions; as in countless other
situations involving clinical or surgical procedures, cell therapy cannot be postponed at
the expense of the patients' health. In Brazil there is a legal inadequacy in respect to
compassionate treatment. And do not forget that the patients cannot wait(2323. Benoit E, O'Donnell TF, Patel AN. Safety and efficacy of autologous
cell therapy in critical limb ischemia: a systematic review. Cell Transplant.
2013;22(3):545-62.,2626. de Santis GC, Ubiali EM, Covas DT. Compassionate use of cell
products. Rev Bras Hematol Hemoter. 2013;35(2):144-5.
27. Rosado-de-Castro PH, Pimentel-Coelho PM, da Fonseca LM, de Freitas
GR, Mendez-Otero R. The rise of cell therapy trials for stroke: review of published
and registered studies. Stem Cells Dev. 2013;22(15):2095-111.-2828. Hansson EM, Lendahl U. Regenerative medicine for the treatment of
heart disease. J Intern Med. 2013;273(3):235-45.).
Cell therapy has flourished in respect to heart diseases in experimental studies on acute myocardial infarction. Soon clinical trials and case reports related to other heart diseases proved the benefits of the procedure. However ten years after the first reports there are still uncertainties about cell therapy(2929. Yousef M, Schannwell CM, Köstering M, Zeus T, Brehm M, Strauer BE. The BALANCE Study: clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction. J Am Coll Cardiol. 2009;53(24):2262-9. Comment in: J Am Coll Cardiol. 2009;53(24):2270-2; J Am Coll Cardiol. 2010;55(3):263-4; author reply 264.,3030. Strauer BE, Steinhoff G. 10 years of intracoronary and intramyocardial bone marrow stem cell therapy of the heart: from the methodological origin to clinical practice. J Am Coll Cardiol. 2011;58(11):1095-104.). Doubts related to cell therapy also extrapolate to the clinical parameters employed in previous studies. These include the use of the left ventricle ejection fraction as a clinical outcome as in many studies. Even without improvements in this parameter being observed, increases in survival and quality of life in many patients subjected to this procedure were demonstrated. The review presented at the congress makes us reflect on the interpretation of results obtained using cell therapy in heart disease. The benefits of the use of cell therapy in the treatment of autoimmune, central nervous system and ophthalmological diseases and for orthopedic complications among others were also demonstrated during the scientific event thereby proving the importance of cell therapy as a new modality of therapy.
In conclusion, cell therapy has proven to be safe and effective in many situations, in particular in peripheral arterial diseases when there is a risk of amputation(2323. Benoit E, O'Donnell TF, Patel AN. Safety and efficacy of autologous cell therapy in critical limb ischemia: a systematic review. Cell Transplant. 2013;22(3):545-62.). This latter example makes us reflect on the current status of the treatment of diverse diseases in which cell therapy may play a leading or supporting role. This procedure remains crucial to relieve the suffering and benefit patients for whom there is no therapeutic option.
References
-
1Xia G, Santostefano KE, Goodwin M, Liu J, Subramony SH, Swanson MS, et al. Generation of neural cells from DM1 induced pluripotent stem cells as cellular model for the study of central nervous system neuropathogenesis. Cell Reprogram. 2013;15(2):166-77.
-
2Zhang Y, Liao S, Yang M, Liang X, Poon MW, Wong CY, et al. Improved cell survival and paracrine capacity of human embryonic stem cell-derived mesenchymal stem cells promote therapeutic potential for pulmonary arterial hypertension. Cell Transplant. 2012;21(10):2225-39.
-
3McMahon DS, Singer PA, Daar AS, Thorsteinsdóttir H. Regenerative medicine in Brazil: small but innovative. Regen Med. 2010;5(6):863-76.
-
4Fraga AM, Sukoyan M, Rajan P, Braga DP, Iaconelli A Jr, Franco JG Jr, et al. Establishment of a Brazilian line of human embryonic stem cells in defined medium: implications for cell therapy in an ethnically diverse population. Cell Transplant. 2011;20(3):431-40.
-
5Landsteiner K, Levine P. On individual differences in human blood. J Exp Med. 1928;47(5):757-75.
-
6Voltarelli JC, Ortega ET, Pasquini R. Transplante de células tronco hematopoéticas. São Paulo; Atheneu: 2009.
-
7Roy S, Gascard P, Dumont N, Zhao J, Pan D, Petrie S, et al. Rare somatic cells from human breast tissue exhibit extensive lineage plasticity. Proc Natl Acad Sci USA. 2013;110(12):4598-603.
-
8Fuhrmann S, Zou C, Levine EM. Retinal pigment epithelium development, plasticity, and tissue homeostasis. Exp Eye Res. 2013 Sep 21. [Epub ahead of print]
-
9Kim HA, Mindos T, Parkinson DB. Plastic fantastic: Schwann cells and repair of the peripheral nervous system. Stem Cells Transl Med. 2013;2(8):553-7.
-
10Knapp D, Tanaka EM. Regeneration and reprogramming. Curr Opin Genet Dev. 2012;22(5):485-93.
-
11Ma T, Xie M, Laurent T, Ding S. Progress in the reprogramming of somatic cells. Circ Res. 2013;112(3):562-74.
-
12Wilkinson AC, Göttgens B. Transcriptional regulation of haematopoietic stem cells. Adv Exp Med Biol. 2013;786:187-212.
-
13Kishore R, Verma SK, Mackie AR, Vaughan EE, Abramova TV, Aiko I, et al. Bone marrow progenitor cell therapy-mediated paracrine regulation of cardiac miRNA-155 modulates fibrotic response in diabetic hearts. PLoS One. 2013;8(4):e60161.
-
14Ruiz MA. A era da terapia celular. Rev Bras Hematol Hemoter. 2005;27(1):4.
-
15Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410(6829):701-5. Comment in: Nature. 2004;428(6983):607-8; Nature. 2004;428(6983):587; Nature. 2001; 410(6829):640-1.
-
16Soares MB, Garcia S, Campos de Carvalho AC, Ribeiro dos Santos R. Cellular therapy in Chagas' disease: potential applications in patients with chronic cardiomyopathy. Regen Med. 2007;2(3):257-64.
-
17Tura BR, Martino HF, Gowdak LH, dos Santos RR, Dohmann HF, Krieger JE, et al. Multicenter randomized trial of cell therapy in cardiopathies - MiHeart Study. Trials. 2007;8:2.
-
18Dohmann HF, Silva SA, Sousa AL, Braga AM, Branco RV, Haddad AF, et al. Multicenter double blind trial of autologous bone marrow mononuclear cell transplantation through intracoronary injection post acute myocardium infarction - MiHeart/AMI study. Trials. 2008;9:41.
-
19Mendez-Otero R, Campos de Carvalho AC. Global update: Brazil. Regen Med. 2012;7(6 Suppl):144-7.
-
20Schoenfeld M, Frishman WH, Leri A, Kajstura J, Anversa P. The existence of myocardial repair: mechanistic insights and enhancements. Cardiol Rev. 2013;21(3):111-20.
-
21Yamaguchi T, Kanayasu-Toyoda T, Uchida E. Angiogenic cell therapy for severe ischemic diseases. Biol Pharm Bull. 2013;36(2):176-81.
-
22Diniz B, Thomas P, Thomas B, Ribeiro R, Hu Y, Brant R, et al. Subretinal implantation of retinal pigment epithelial cells derived from human embryonic stem cells: improved survival when implanted as a monolayer. Invest Ophthalmol Vis Sci. 2013;54(7):5087-96.
-
23Benoit E, O'Donnell TF, Patel AN. Safety and efficacy of autologous cell therapy in critical limb ischemia: a systematic review. Cell Transplant. 2013;22(3):545-62.
-
24Benoit E, O'Donnell TF Jr, Kitsios GD, Iafrati MD. Improved amputation-free survival in unreconstructable critical limb ischemia and its implications for clinical trial design and quality measurement. J Vasc Surg. 2012;55(3):781-9.
-
25Anversa P, Kajstura J, Rota M, Leri A. Regenerating new heart with stem cells. J Clin Invest. 2013;123(1):62-70.
-
26de Santis GC, Ubiali EM, Covas DT. Compassionate use of cell products. Rev Bras Hematol Hemoter. 2013;35(2):144-5.
-
27Rosado-de-Castro PH, Pimentel-Coelho PM, da Fonseca LM, de Freitas GR, Mendez-Otero R. The rise of cell therapy trials for stroke: review of published and registered studies. Stem Cells Dev. 2013;22(15):2095-111.
-
28Hansson EM, Lendahl U. Regenerative medicine for the treatment of heart disease. J Intern Med. 2013;273(3):235-45.
-
29Yousef M, Schannwell CM, Köstering M, Zeus T, Brehm M, Strauer BE. The BALANCE Study: clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction. J Am Coll Cardiol. 2009;53(24):2262-9. Comment in: J Am Coll Cardiol. 2009;53(24):2270-2; J Am Coll Cardiol. 2010;55(3):263-4; author reply 264.
-
30Strauer BE, Steinhoff G. 10 years of intracoronary and intramyocardial bone marrow stem cell therapy of the heart: from the methodological origin to clinical practice. J Am Coll Cardiol. 2011;58(11):1095-104.
Publication Dates
-
Publication in this collection
2013
History
-
Received
24 Aug 2013 -
Accepted
01 Sept 2013