Therapeutic angiogenesis using stem cell

Last updated date: 12-Jun-2023

Originally Written in English

Therapeutic Angiogenesis Using Stem Cell



Stem cells are undifferentiated cells that can turn into specific cells, as the body needs them. Scientists and doctors are interested in stem cells as they help to explain how some functions of the body work, and how they sometimes go wrong.

Ischemic diseases, which are caused by a reduction of blood supply that results in reduced oxygen transfer and nutrient uptake, are becoming the leading cause of disabilities and deaths. Therapeutic angiogenesis is key for the treatment of these diseases. Stem cells have been used in animal models and clinical trials to treat various ischemic diseases. 


What Is Stem Cell?

Stem Cell

Stem cells are the raw materials of the body, the cells that give rise to all other cells with specific roles. Under the correct conditions, stem cells divide to generate new cells known as daughter cells in the body or in a laboratory.

These daughter cells may differentiate into additional stem cells or become specialized cells with a more particular role, such as blood cells, brain cells, heart muscle cells, or bone cells. No other cell in the body has the potential to naturally produce new cell types.


Why Is There Such an Interest in Stem Cells?

Stem Cell drugs

Researchers hope stem cell studies can help to:

  1. Increase understanding of how diseases occur. By watching stem cells mature into cells in bones, heart muscle, nerves, and other organs and tissue, researchers may better understand how diseases and conditions develop.
  2. Generate healthy cells to replace cells affected by disease (regenerative medicine). Stem cells can be directed to become particular cells that can be employed in humans to regenerate and repair tissues damaged or affected by disease. People with spinal cord injuries, type 1 diabetes, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, heart disease, stroke, burns, cancer, and osteoarthritis may benefit from stem cell therapy. Stem cells may be able to be developed into new tissue for use in transplantation and regenerative medicine. Researchers are continuing to learn more about stem cells and their uses in transplant and regenerative medicine.
  3. Test new drugs for safety and effectiveness. Researchers can utilize some types of stem cells to evaluate medications for safety and quality before employing them in humans. This form of testing will almost certainly have the most immediate impact on drug development for cardiac toxicity assessment. New fields of research include the effectiveness of testing new medications utilizing human stem cells that have been programmed into tissue-specific cells. For appropriate drug testing, cells must be trained to acquire attributes of the kind of cells targeted by the medication. Techniques for programming cells to become certain cells are being researched. For instance, nerve cells could be generated to test a new drug for a nerve disease. Tests could show whether the new drug had any effect on the cells and whether the cells were harmed.


What Are Stem Cell Lines & Why Do Researchers Want to Use Them?

Stem Cell Lines

A stem cell line is a group of cells that all descend from a single original stem cell and are grown in a lab. Cells in a stem cell line keep growing but don't differentiate into specialized cells. Ideally, they remain free of genetic defects and continue to create more stem cells. Clusters of cells can be taken from a stem cell line and frozen for storage or shared with other researchers.


Where Do Stem Cells Come From?

Stem cells illustration

There are several sources of stem cells:

  • Embryonic stem cells. These stem cells are derived from 3 to 5 day old embryos. At this stage, an embryo is known as a blastocyst and has around 150 cells. These are pluripotent stem cells, which means they can proliferate and form any type of cell in the body. Because of their adaptability, embryonic stem cells can be employed to restore or repair damaged tissue and organs.
  • Adult stem cells. Most adult tissues, such as bone marrow and fat, contain a limited amount of these stem cells. Adult stem cells, in comparison to embryonic stem cells, have a more limited potential to give birth to diverse body cells. Adult stem cells were considered to only be capable of producing comparable types of cells until recently. For example, researchers previously believed that stem cells found in bone marrow could only give birth to blood cells.


However, new research reveals that adult stem cells may generate a variety of cell types. Bone marrow stem cells, for example, may be able to become bone or heart muscle cells. This study has resulted in early-stage clinical studies to assess the utility and safety of the product in humans. Adult stem cells, for example, are currently being investigated in persons suffering from neurological or cardiovascular disease. Adult cells have been modified to exhibit embryonic stem cell characteristics. Using genetic reprogramming, scientists successfully turned ordinary adult cells into stem cells. Researchers can reprogram adult cells to behave like embryonic stem cells by modifying their DNA.


This novel technology may allow for the use of reprogrammed cells rather than embryonic stem cells, as well as the prevention of immune system rejection of the new stem cells. However, scientists are unsure if employing changed adult cells would have a negative impact on humans. Researchers have been able to take regular connective tissue cells and reprogram them to become functional heart cells. In studies, animals with heart failure that were injected with new heart cells experienced improved heart function and survival time.


  • Perinatal stem cells. Researchers detected stem cells in both amniotic fluid and umbilical cord blood. These stem cells have the capacity to differentiate into many types of cells. Amniotic fluid fills the sac in the uterus that surrounds and protects the growing embryo. Researchers discovered stem cells in amniotic fluid samples taken from pregnant women for diagnosis or treatment, a technique known as amniocentesis.


Types of Stem Cells

Researchers categorize stem cells, according to their potential to differentiate into other types of cells.

Embryonic stem cells are the most potent, as their job is to become every type of cell in the body.

The full classification includes:

  • Totipotent: These stem cells can differentiate into all possible cell types. The first few cells that appear as the zygote starts to divide are totipotent.
  • Pluripotent: These cells can turn into almost any cell. Cells from the early embryo are pluripotent.
  • Multipotent: These cells can differentiate into a closely related family of cells. Adult hematopoietic stem cells, for example, can become red and white blood cells or platelets.
  • Oligopotent: These can differentiate into a few different cell types. Adult lymphoid or myeloid stem cells can do this.
  • Unipotent: These can only produce cells of one kind, which is their own type. However, they are still stem cells because they can renew themselves. Examples include adult muscle stem cells.

Embryonic stem cells are considered pluripotent instead of totipotent because they cannot become part of the extra-embryonic membranes or the placenta.


Mechanism of Stem Cell Participation

Mechanism of Stem Cell

Stem cells assist in angiogenesis to heal tissue ischemia by releasing angiogenic factors and/or developing into vascular lineage. Mesenchymal stem cells (MSCs), for example, release angiogenic paracrine factors including VEGF, bFGF, and PDGF, which drive neovessel creation. Some researchers have also discovered that MSCs can develop into endothelial lineages and/or exhibit endothelial lineage markers. Previously, researchers discovered that ECs produced from human iPSCs (iPSC-ECs) release angiogenic factors such bFGF, VEGF, and angiopoietin-1 to the same extent as native ECs. Furthermore, the iPSC-ECs can integrate functionally into the perivascular region.

Human endothelial progenitor cells (EPCs) and Human Mononuclear Cells (MNC) can differentiate into endothelial lineage by forming neovasculature that functionally anastamose with host circulation. These varying mechanisms enable stem cells to differentiate and/or to incorporate into vasculature or release paracrine factors to stimulate host-derived angiogenesis.


Before Therapeutic Stem Cell Angiogenesis

Therapeutic Stem Cell

The pre-operative visit may take several hours. You may also wish to bring a family member who will be assisting with your care.

The following activities are necessary before surgery:

  • Pre-registration
  • Blood work, EKG, urinalysis (You do not need to fast for blood work)
  • Chest X-ray
  • Meet the nurse practitioner or physician assistant
  • Anesthesia evaluation
  • Meet the nurse coordinator

The nurse coordinator will go over:

  • Pre-operative, peri-operative, and post-operative process of cardiac surgery
  • Medications to continue or stop
  • Incentive spirometer
  • Sternal precautions
  • Pain management
  • Diet and nutrition post-surgery
  • Other restrictions during your recovery
  • Discharge planning: Home health care, rehab, or a skilled nursing facility (SNF) as needed.


What Therapeutic Stem Cell Angiogenesis Can Treat?

Myocardial Infarction

  • Treatment of PAD using MNCs and EPCs.

Cardiologists first demonstrated EPCs integrated with host capillary vessel walls and formed capillaries in the ischemic limbs. Doctors provided evidence that BM-MNCs derived from Histopaque density gradient centrifugation augmented neovascularization by inducing collateral vessel formation and blood perfusion. In many studies, the authors observed notable improvement in angiographic score, an increase in capillary density, an increase in transcutaneous oxygen pressure, and a reduction in skin ulceration.

 The angiographic score was a quantitative analysis of collateral vessel development from angiogram films. They reported an increase in microvessel density and more extensive expression of FGF and VEGF when the combined therapy was performed, compared with administration of each treatment separately. 

Similar improvements in capillary density and blood perfusion were reported also when Histopaque gradient-isolated BM-MNCs were transplanted in mice with ischemic skeletal muscle.

  • Treatment of PAD using MSCs.

As for MSCs, a number of studies have been performed to show their therapeutic effects. They showed that MSCs were able to improve limb function, reduce autoamputation, and attenuate muscle atrophy and fibrosis. 

The authors demonstrated that the therapeutic benefits were due to paracrine mechanisms, especially through the release of bFGF and VEGF from the cells. In a related study, the same group also provided a full spectrum of cytokine genes expressed by MSCs to examine the paracrine mechanisms. Importantly, they demonstrated that injection of cells was not required for therapeutic benefits. 

Instead, treatment with conditioned media from MSCs was sufficient to mediate arteriogenesis and enhance collateral flow, which provides supportive evidence of the paracrine effects of MSCs. The authors also compared the angiogenic potency of MSCs and BM-MNCs under an ischemic environment in vivo. MSCs appeared to have more therapeutic effect than MNCs and also differentiate into ECs and vascular smooth muscle cells by detecting Vol willbrand factor (Vwf(and smooth muscle α-actin, respectively. 

  • Treatment of PAD using Pluripotent stem cells (PSCs) -derived endothelial cell.

ECs differentiated from human ESCs (ESC-ECs) and Human induced pluripotent stem cells iPSCs (iPSC-ECs) have also been tested. When the cells were delivered to the ischemic limb, the tissue demonstrated improved limb salvage and blood perfusion, along with increased capillary and arteriole densities. Since mature vessels are composed not only of ECs but also smooth muscle cells. When delivered together, there were reportedly synergistic effects in neovascularization and blood perfusion, compared with when only one cell type was delivered. To track the kinetics of cell survival, doctors used bioluminescence imaging to track VE-cadherin+ murine ESC-ECs delivered to the ischemic hindlimb by intramuscular, intrafemoral artery, or intrafemoral vein injection. 

The results showed that ESC-ECs delivered by all three modalities localized in ischemic limb, but the systemically delivered cells resulted in greater improvement in limb perfusion and neovascularization, compared with intramuscular delivery. These data further support the feasibility of using human iPSC-ECs in developing novel cell therapies for patients with PAD.

  • Myocardial Infarction.

Another ischemic CVD is MI, which affects more than seven million people in the United States alone . MI results from obstruction of the coronary arteries, leading to prolonged ischemia and death of cardiomyocytes. The massive loss of cardiomyocytes, vascular cells, and interstitial cells (in the order of 1 billion) contributes to the frequent hospitalizations and premature death of patients undergoing traditional therapies. It is widely agreed that the human myocardium has low regenerative capacity that associates with inadequate compensation for severe loss of heart muscle. Therefore, regenerative approaches to restore myocardium are in urgent need and have attracted a large amount of preclinical and clinical testing.

Preclinical MI models are commonly generated from occlusion of the left anterior descending coronary artery, followed by reperfusion. To repair the heart, early studies transplanted fetal, neonatal, and adult cardiomyocytes and showed stable grafts in the injured hearts. However, because of their limited availability, researchers turned to stem cells as alternative sources to improve cardiac function. The main approaches to deliver the cells include transepicardial injection into the myocardium, transendocardial injection using percutaneous catheters, and intracoronary infusion using angioplasty balloons.

  • Treatment of MI using MNCs.

Adult stem cells have been extensively tested in the preclinical setting. For basic research and clinical trials, the major source of adult stem cells is the bone marrow. In small and large animal models, BM-MNCs have been shown to be able to reduce infarct size and improve left ventricular function and perfusion, along with modest improvements in physiological and anatomical parameters in human patients such as peak systolic displacement, peak systolic strain, as well as left ventricular ejection fraction (LVEF). New endothelial and smooth muscle cells were also identified in coronary vessels. Regional blood flow, capillary densities were significantly increased, with improved cardiac function. The data also revealed that BM-MNCs were incorporated into more than 30% of neocapillaries and 8% of macrophages. 

  • Treatment of MI using MSCs.

As for MSCs, a number of rodent and swine models have been used to prove the ability of MSCs to engraft and differentiate in the heart. Doctors injected autologous porcine Di-I-labeled MSCs expanded from bone marrow aspirates into post-MI myocardium and observed successful engraftment of these cells in the scarred myocardium, as well as the expression of cardiomyocyte markers such as α-actin, tropomyosin, troponin T, myosin heavy chain, and phospholamban at 2 wk post-injection. 



Cardiovascular disease

Cardiovascular disease (CVD) is the major cause of mortality and morbidity among Americans and Veterans, accounting for one in every three deaths and a $196 billion hospital burden. Tissue ischemia linked with coronary heart disease and peripheral artery disease (PAD) in particular accounts for more than half of all CVDs. Although the quality of life of patients with CVDs has improved in recent decades as a result of medication therapy and organ transplantation, there is still a great need to find superior treatments for the treatment of tissue ischemia. As a result, stem cell-based techniques to promoting angiogenesis for the enhancement of tissue function and/or blood perfusion seem attractive.

 Adult bone marrow-derived mononuclear cells (BM-MNCs), endothelial progenitor cells (EPCs), and pluripotent stem cell-derived endothelial cells have all been studied for their ability to promote angiogenesis in ischemic CVDs (PSC-ECs). In this review, we will look at the current state of stem cell therapy in preclinical and clinical settings for the treatment of peripheral arterial disease (PAD) and myocardial infarction (MI).