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Review Article
Regeneration of Cardiomyocytes by Using Bone Marrow Derived Stem Cell
Transplantation and Other Factors Involved in Heart Repair
Pablo González


Abstract:

 The heart is a very important organ in our body because it is in charge of pumping the

oxygenated blood through the veins and capillaries. One way it can be affected is by suffering a

heart attack. A heart attack can affect the heart by lowering its ability to pump and not carrying

the needed amount of oxygen through the body. If the heart continues at that rate its cells will be

damaged from lack of oxygen and the individual will suffer from heart failure. There are still no

cures for heart failure, although there are treatments. One very important treatment is Bone

Marrow Cell transplantation which consists of transplanting derived stem cells from the bone

marrow and injecting them into the cardiomyocytes. Stem cells will differentiate into heart cells,

taking the place of the destroyed ones. Transplantation therapy still needs more research, but it

has shown significant results in the regeneration of cardiomyocytes. Other types of heart therapy

are Vascular Endothelial Growth Factor intravenous injection and Drug Combination therapy.

The first one consists of injecting the myocardium with vascular endothelial growth factor which

will have an angiogenic and therapeutic effect. The second treatment requires the administration

of drugs such as statins, after the infarction to improve the viability of bone marrow derived stem

cell transplantation.


Introduction:                                           The heart, a muscle approximately the size

                                                      of a fist, is a vital organ. It contains four

                                                      cavities: two atria, and two ventricles, and


                                                 1
pumps oxygenated blood through all the                 The results of this treatment have shown to

veins and capillaries in our body. The cells          improve the cardiac function. However,

that make up the heart are called myocytes            many have postulated that the mechanism of

or cardiomyocytes. When these cells suffer            action of BMC therapy is via the release of

the consequences of a heart attack, it is very        paracrine factors such as vascular

difficult for the heart to replenish or               endothelial growth factor. Aside from this,

regenerate them causing heart failure and             research has shown that implanted cells have

possible death.                                       not been shown to survive in myocardium

                                                      for long periods (Yeghiazarians 2009).
  Currently there is not a cure for heart

failure, but there are still treatments such as        Discussed in this review article are the

medicines and a healthier lifestyle (National         current experiments and views on

Heart Lung and Blood Institute 2010). A               transplantation of bone marrow derived stem

healthier life style includes doing exercise,         cells on infracted hearts and the different

eating healthy, managing stress, ect. One             factors that affect them.

new and very important treatment is the
                                                      What is heart failure?
transplantation of bone marrow derived cells

(BMCs). This treatment consists of                     When someone suffers a myocardial

transplanting stem cells derived from the             infarction (heart attack), the heart may

bone marrow to the heart. When                        become scarred and lose its ability to pump

transplanted, the cells begin to differentiate        enough blood through the body. A heart

into heart cells (cardiomyocytes), filling the        attack occurs when plaque builds up inside

place of the previously destroyed ones.               the coronary arteries, cutting off the oxygen

                                                      rich blood to the heart. This is called



                                                  2
coronary heart disease and it is the number           Bone Marrow Derived Cells:

one cause of heart attacks. If blood flow is
                                                       To solve the problems previously stated
not restored quickly, the section of heart
                                                      scientists are experimenting with the
muscle without oxygen begins to die. The
                                                      injection or extract of the cells derived from
part of the heart that becomes damaged is
                                                      the bone marrow into the damaged heart.
known as the myocardium. This is the
                                                      These specific types of cells are called stem
muscular middle layer of the wall of the
                                                      cells, which are undifferentiated cells that
heart that stimulates the heart contractions to
                                                      can develop into any type of cells in the
pump blood.
                                                      body. There are many types of stem cells in

 When the heart suffers a myocardial                  the body. Some of these are: adipose derived

infarction, its pumping becomes weaker                stem cells (ADSCs), cardiac stem cells

progressively and this opens the pathway for          (CSCs), peripheral blood derived cells,

heart failure. Heart failure is a progressive         embryonic stem cells (ES), and induced

disorder in which the heart can not pump              pluripotent stem cells (iPS) (Mingliang

enough blood to meet the body’s demand. It            2009). The problem with these other types

is estimated that yearly17 million of the             of stem cells is that either they cause an

people worldwide die of cardiovascular                adverse effect on the heart, or that they can

diseases, specifically heart attacks and              not be used because of ethical

strokes . Despite advances in medicine, there         considerations. Bone marrow derived cells

are currently no approaches in clinical               (BMC) are currently the most widely used in

practice that replace myocardial scar with            clinical trials because they are not as

functioning contractile tissue (Yeghizarians          controversial and are the ones that exhibit

2009).                                                the desired effect (Mingliang 2009).



                                                  3
To prove that the BMC therapy would                 affected myocardium and that it attracts

improve the condition of the heart, scientists       stem cells to that area to promote

in a research laboratory often induce heart          reconstruction of myocardial growth

attacks on a mouse or rat model to study the         network (Hoeben 2004). VGEF can increase

therapy. The way they do this is by placing a        permeability of capillary wall, activate

ligature around a major blood vessel                 matrix metalloproteinase, and promote

connected to the heart muscle. This deprives         endothelial cell proliferation and migration

the cardiomyocytes of their oxygen causing           (Mingliang 2009). The therapy consists on

the heart attack. One of the findings of the         injecting the myocardium with VEGF to

scientists when they were using the mouse            induce angiogenesis after intramyocardial

model was that the mice that received the            transplantation. Researchers show that

transplanted cells survived in greater               VEGF increases angiogenesis, has a longer

numbers than mice with heart attacks that            duration, and is probably necessary for the

did not receive the mouse stem cells                 preservation of the myocardium and

(National Institute of Health).                      limitation of cellular destruction when the

                                                     cells are deprived of oxygen (Hoeben 2004).
How is Vascular Endothelial Growth
                                                     In other words, VGEF helps improve
Factor (VGEF) Related to Cardiac
                                                     myocardial ischemia because there is an
Repair?
                                                     important relationship between VGEF,

  VGEF is a molecule that has been found             angiogenesis, and recovery for cardiac cell

to be an inducer of Angiogenesis, which              therapy (Payne 2007).

indicates wound healing. Scientist believe

that VGEF molecule is secreted after

myocardial infarction in the region of the


                                                 4
What Are the Effects of Drug                         Discussion:

Combination Therapy on Infarcted
                                                       There seems to be many new ideas
Hearts?
                                                     involving BMC therapy along with other

 This type of therapy consists on the                factors on how to treat heart diseases such as

administration of drugs to a patient after           myocardial infarctions, but some of them

suffering from myocardial infarction. There          still need to be further tested for

are many types of drugs that can be applied,         consistency. Even though tests have shown

an example would be statins. Statins lower           their effectiveness on mouse models and

plasma cholesterol by blocking the action of         patients, it cannot be concluded that BMC

a chemical in the liver that is necessary for        transplantation will cure heart failure. Some

the production of cholesterol (Ramasubbu             of these ideas include the combination of

2008). The use of these types of drugs               drugs right after the BMC transplantation, or

lowers the risks of heart attacks and strokes.       the intravenous delivery of VEGF-A, which

In addition to inhibiting myocyte                    showed a significant improvement (Hoeben

hypertrophy, statins affect myocardial               2004). VEGF-blocking therapy appears

fibrosis (Ramasubbu 2008). Yang et.al used           promising in the treatment of cancer,

simvastatin in the combination therapy and           although, the clinical trials are still at an

obtained very good curative effects. Other           early stage, and combination therapy seems

scientists have used different drugs such as         more effective because both endothelial cell

angiotensin converting enzyme (ACE)                  and tumor cell are targeted.

inhibitor after an infarction and have
                                                       In conclusion, transplanting bone marrow
obtained similar results on the regeneration
                                                     stem cells to the damaged heart has been
of the myocardium.
                                                     proven to give beneficial results, but is even


                                                 5
more effective when it is combined with           Vascular Endothelial Growth Factor,
                                                  Angiogenesis, and Cardiac Repair After
vascular endothelial growth factor therapy        Muscle Cell Transplantation into Ischemic
                                                  Hearts.[Internet]Cited November 15, 2011.
or drug combination therapy. It has opened
                                                  - Sambasiva K. R. S., Ananda K., Sai K,
the pathway for new myocardial infarction
                                                  Berrocal Ruben, Rao K.S.April 3, 2011.
treatments that will make an improvement          Myocardial infarction and stem
                                                  cells.[Internet]Cited October 7, 2011.
on society.
                                                  - Strauer Bodo et.al. Regeneration of
                                                  Human Infarcted Heart Muscle by
References:                                       Intracoronary Autologous Bone Marrow
                                                  Cell Transplantation in Chronic Coronary
-Boyle Andrew. Et.al. September 12,               Artery Disease.2005.Journal of the
2011.Myocardial Production and Release of         American College of Cardiology.Elsevier
MCP-1 and SDF-1 Following Myocardial              Inc.Vol. 46, No.9.Cited October 13, 2011.
Infarction: Differences Between Mice and          -Strauer Bodo, Yousef Muhammad,
Man.[Internet]Cited November 14, 2011.            Schannwell Christiana.April 16, 2010.The
-Hoeben Ann, Landuyt Bart, Highley                Accute and Long Term Effects of
Martin, Wildiers Hans, Oosterom Aallan,           Intracoronary Stem Cell Transplantation in
Bruijn Ernest.2004. Vascular Endothellial         191 Patients With Chronic Heart Failure:
Growth Factor and                                 The STAR-Heart Study.European Journal of
Angiogenesis.Pharmacological                      Heart Failure[Internet]Cited Novenber 14,
Reviews.Vol. 56, No.4.Cited November 14,          2011.
2011.                                             - Can Stem Cells Repair a Damaged Heart?
- Mingliang Ren, Zhang Bo, Wang                   In Stem Cell Information [World Wide Web
Zhengguo.June 15,2011. Stem Cells for             site]. Bethesda, MD: National Institutes of
Cardiac Repair: Status, Mechanisms, and           Health, U.S. Department of Health and
New Strategies[Internet]Cited October 6,          Human Services, 2009. [Internet] Cited
2011.                                             November 26, 2011.

-National Heart Lung and Blood                    - Yeghizarians Yerem. Et.al. Imjection of
Institute.January 1, 2010.What is heart           Bone Marrow Extract Into Infarcted Hearts
Failure?.[Internet]Cited November 14, 2011.       Results in Functional Improvement
                                                  Comparable to Intact Cell Therapy. March
-Payne Thomas, Oshima Hideki, Okada               25, 2009. [Internet] Cited November 15,
Masaho, Momoi Nobuo, Tobita Kimimasa,             2011.
Keller Bradley, Peng Hairong, Huard
Johnny.2007.A Relationship Between                - Ramasubbu Kumudha, Estep Jerry, White
                                                  Donna, Deswall Anita, Mann Douglas.


                                              6
Experimental and Clinical Basis for the Use
of Statins in Patients With Ischemic and No
ischemic Cardiomyopathy. January 24,
2008. Journal of the American College of
Cardiology. Vol. 51, issue 4. Cited
November 30,2011.




                                              7

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Regeneration of cardiomyocytes using bone marrow derived stem cell transplantation and other factors involved in heart repair.

  • 1. Review Article Regeneration of Cardiomyocytes by Using Bone Marrow Derived Stem Cell Transplantation and Other Factors Involved in Heart Repair Pablo González Abstract: The heart is a very important organ in our body because it is in charge of pumping the oxygenated blood through the veins and capillaries. One way it can be affected is by suffering a heart attack. A heart attack can affect the heart by lowering its ability to pump and not carrying the needed amount of oxygen through the body. If the heart continues at that rate its cells will be damaged from lack of oxygen and the individual will suffer from heart failure. There are still no cures for heart failure, although there are treatments. One very important treatment is Bone Marrow Cell transplantation which consists of transplanting derived stem cells from the bone marrow and injecting them into the cardiomyocytes. Stem cells will differentiate into heart cells, taking the place of the destroyed ones. Transplantation therapy still needs more research, but it has shown significant results in the regeneration of cardiomyocytes. Other types of heart therapy are Vascular Endothelial Growth Factor intravenous injection and Drug Combination therapy. The first one consists of injecting the myocardium with vascular endothelial growth factor which will have an angiogenic and therapeutic effect. The second treatment requires the administration of drugs such as statins, after the infarction to improve the viability of bone marrow derived stem cell transplantation. Introduction: The heart, a muscle approximately the size of a fist, is a vital organ. It contains four cavities: two atria, and two ventricles, and 1
  • 2. pumps oxygenated blood through all the The results of this treatment have shown to veins and capillaries in our body. The cells improve the cardiac function. However, that make up the heart are called myocytes many have postulated that the mechanism of or cardiomyocytes. When these cells suffer action of BMC therapy is via the release of the consequences of a heart attack, it is very paracrine factors such as vascular difficult for the heart to replenish or endothelial growth factor. Aside from this, regenerate them causing heart failure and research has shown that implanted cells have possible death. not been shown to survive in myocardium for long periods (Yeghiazarians 2009). Currently there is not a cure for heart failure, but there are still treatments such as Discussed in this review article are the medicines and a healthier lifestyle (National current experiments and views on Heart Lung and Blood Institute 2010). A transplantation of bone marrow derived stem healthier life style includes doing exercise, cells on infracted hearts and the different eating healthy, managing stress, ect. One factors that affect them. new and very important treatment is the What is heart failure? transplantation of bone marrow derived cells (BMCs). This treatment consists of When someone suffers a myocardial transplanting stem cells derived from the infarction (heart attack), the heart may bone marrow to the heart. When become scarred and lose its ability to pump transplanted, the cells begin to differentiate enough blood through the body. A heart into heart cells (cardiomyocytes), filling the attack occurs when plaque builds up inside place of the previously destroyed ones. the coronary arteries, cutting off the oxygen rich blood to the heart. This is called 2
  • 3. coronary heart disease and it is the number Bone Marrow Derived Cells: one cause of heart attacks. If blood flow is To solve the problems previously stated not restored quickly, the section of heart scientists are experimenting with the muscle without oxygen begins to die. The injection or extract of the cells derived from part of the heart that becomes damaged is the bone marrow into the damaged heart. known as the myocardium. This is the These specific types of cells are called stem muscular middle layer of the wall of the cells, which are undifferentiated cells that heart that stimulates the heart contractions to can develop into any type of cells in the pump blood. body. There are many types of stem cells in When the heart suffers a myocardial the body. Some of these are: adipose derived infarction, its pumping becomes weaker stem cells (ADSCs), cardiac stem cells progressively and this opens the pathway for (CSCs), peripheral blood derived cells, heart failure. Heart failure is a progressive embryonic stem cells (ES), and induced disorder in which the heart can not pump pluripotent stem cells (iPS) (Mingliang enough blood to meet the body’s demand. It 2009). The problem with these other types is estimated that yearly17 million of the of stem cells is that either they cause an people worldwide die of cardiovascular adverse effect on the heart, or that they can diseases, specifically heart attacks and not be used because of ethical strokes . Despite advances in medicine, there considerations. Bone marrow derived cells are currently no approaches in clinical (BMC) are currently the most widely used in practice that replace myocardial scar with clinical trials because they are not as functioning contractile tissue (Yeghizarians controversial and are the ones that exhibit 2009). the desired effect (Mingliang 2009). 3
  • 4. To prove that the BMC therapy would affected myocardium and that it attracts improve the condition of the heart, scientists stem cells to that area to promote in a research laboratory often induce heart reconstruction of myocardial growth attacks on a mouse or rat model to study the network (Hoeben 2004). VGEF can increase therapy. The way they do this is by placing a permeability of capillary wall, activate ligature around a major blood vessel matrix metalloproteinase, and promote connected to the heart muscle. This deprives endothelial cell proliferation and migration the cardiomyocytes of their oxygen causing (Mingliang 2009). The therapy consists on the heart attack. One of the findings of the injecting the myocardium with VEGF to scientists when they were using the mouse induce angiogenesis after intramyocardial model was that the mice that received the transplantation. Researchers show that transplanted cells survived in greater VEGF increases angiogenesis, has a longer numbers than mice with heart attacks that duration, and is probably necessary for the did not receive the mouse stem cells preservation of the myocardium and (National Institute of Health). limitation of cellular destruction when the cells are deprived of oxygen (Hoeben 2004). How is Vascular Endothelial Growth In other words, VGEF helps improve Factor (VGEF) Related to Cardiac myocardial ischemia because there is an Repair? important relationship between VGEF, VGEF is a molecule that has been found angiogenesis, and recovery for cardiac cell to be an inducer of Angiogenesis, which therapy (Payne 2007). indicates wound healing. Scientist believe that VGEF molecule is secreted after myocardial infarction in the region of the 4
  • 5. What Are the Effects of Drug Discussion: Combination Therapy on Infarcted There seems to be many new ideas Hearts? involving BMC therapy along with other This type of therapy consists on the factors on how to treat heart diseases such as administration of drugs to a patient after myocardial infarctions, but some of them suffering from myocardial infarction. There still need to be further tested for are many types of drugs that can be applied, consistency. Even though tests have shown an example would be statins. Statins lower their effectiveness on mouse models and plasma cholesterol by blocking the action of patients, it cannot be concluded that BMC a chemical in the liver that is necessary for transplantation will cure heart failure. Some the production of cholesterol (Ramasubbu of these ideas include the combination of 2008). The use of these types of drugs drugs right after the BMC transplantation, or lowers the risks of heart attacks and strokes. the intravenous delivery of VEGF-A, which In addition to inhibiting myocyte showed a significant improvement (Hoeben hypertrophy, statins affect myocardial 2004). VEGF-blocking therapy appears fibrosis (Ramasubbu 2008). Yang et.al used promising in the treatment of cancer, simvastatin in the combination therapy and although, the clinical trials are still at an obtained very good curative effects. Other early stage, and combination therapy seems scientists have used different drugs such as more effective because both endothelial cell angiotensin converting enzyme (ACE) and tumor cell are targeted. inhibitor after an infarction and have In conclusion, transplanting bone marrow obtained similar results on the regeneration stem cells to the damaged heart has been of the myocardium. proven to give beneficial results, but is even 5
  • 6. more effective when it is combined with Vascular Endothelial Growth Factor, Angiogenesis, and Cardiac Repair After vascular endothelial growth factor therapy Muscle Cell Transplantation into Ischemic Hearts.[Internet]Cited November 15, 2011. or drug combination therapy. It has opened - Sambasiva K. R. S., Ananda K., Sai K, the pathway for new myocardial infarction Berrocal Ruben, Rao K.S.April 3, 2011. treatments that will make an improvement Myocardial infarction and stem cells.[Internet]Cited October 7, 2011. on society. - Strauer Bodo et.al. Regeneration of Human Infarcted Heart Muscle by References: Intracoronary Autologous Bone Marrow Cell Transplantation in Chronic Coronary -Boyle Andrew. Et.al. September 12, Artery Disease.2005.Journal of the 2011.Myocardial Production and Release of American College of Cardiology.Elsevier MCP-1 and SDF-1 Following Myocardial Inc.Vol. 46, No.9.Cited October 13, 2011. Infarction: Differences Between Mice and -Strauer Bodo, Yousef Muhammad, Man.[Internet]Cited November 14, 2011. Schannwell Christiana.April 16, 2010.The -Hoeben Ann, Landuyt Bart, Highley Accute and Long Term Effects of Martin, Wildiers Hans, Oosterom Aallan, Intracoronary Stem Cell Transplantation in Bruijn Ernest.2004. Vascular Endothellial 191 Patients With Chronic Heart Failure: Growth Factor and The STAR-Heart Study.European Journal of Angiogenesis.Pharmacological Heart Failure[Internet]Cited Novenber 14, Reviews.Vol. 56, No.4.Cited November 14, 2011. 2011. - Can Stem Cells Repair a Damaged Heart? - Mingliang Ren, Zhang Bo, Wang In Stem Cell Information [World Wide Web Zhengguo.June 15,2011. Stem Cells for site]. Bethesda, MD: National Institutes of Cardiac Repair: Status, Mechanisms, and Health, U.S. Department of Health and New Strategies[Internet]Cited October 6, Human Services, 2009. [Internet] Cited 2011. November 26, 2011. -National Heart Lung and Blood - Yeghizarians Yerem. Et.al. Imjection of Institute.January 1, 2010.What is heart Bone Marrow Extract Into Infarcted Hearts Failure?.[Internet]Cited November 14, 2011. Results in Functional Improvement Comparable to Intact Cell Therapy. March -Payne Thomas, Oshima Hideki, Okada 25, 2009. [Internet] Cited November 15, Masaho, Momoi Nobuo, Tobita Kimimasa, 2011. Keller Bradley, Peng Hairong, Huard Johnny.2007.A Relationship Between - Ramasubbu Kumudha, Estep Jerry, White Donna, Deswall Anita, Mann Douglas. 6
  • 7. Experimental and Clinical Basis for the Use of Statins in Patients With Ischemic and No ischemic Cardiomyopathy. January 24, 2008. Journal of the American College of Cardiology. Vol. 51, issue 4. Cited November 30,2011. 7