RegenerativeMedicineThearapy

GUIDE BOOK

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Regenerative

Medicine

Introduction

While modern age has seen significant medical advances, there are increasingly more patients with lifestyle-related diseases such as diabetes mellites, heart disease, stroke, hypertension, obesity, and dyslipidemia as well as many patients with refractory diseases. These diseases are difficult to cure completely, and key treatments of these diseases have been symptomatic treatments, which only control or relieve symptoms with medication, so far. However, we have a new therapeutic option. That is “stem cell regenerative medicine treatment.” Currently, the regenerative medicine draws the most attention in the medical industry. This field is rapidly advancing, and new achievements are reported from all over the world every day. The regenerative medicine, a therapy using cells and tissues, paves the way for new treatment of dis-eases that have been refractory to existing treatment. Human body is made up of about 60 trillion cells, each of which has its own role for body function as seen in muscles and nerves. We also have special cells that do not have a specific role but have a potential to develop into differ-ent types of cells. These are “stem cells.” “Stem cells” have an ability to repair or regenerate cells and tissues that do not function because of diseases. In “stem cell regenerative medicine treatment”, stem cells are isolated from lypocytes collected from a patient, cultured, and transplanted back to the patient to improve the patient’ s condition. Because “ the stem cells” are isolated from the patient’ s own lipocytes, it is a very safe and reliable thera-py, with no possible rejection reaction.

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Our body is made up of about 60 trillion cells of 200 or more types. These cells originate in one single “ferti l ized egg.” This ferti l ized egg multiplies by repeating cell division many times. During this process, cells are differentiated and develop forms and functions that are suitable for their roles. Cells continue to grow and differentiate into cells with their own roles, such as muscle cells and nerve cells (※ see Figure 1). Some cells like skin and blood cells have a short life and have an ability to produce and replace cells to maintain the tissue. Others have an ability to repair cells and supplement lost function when you are injured or have a disease. The cells having these important roles are called “stem cells.” Thanks to these “stem cells,” we can grow from the fertilized egg and maintain our body when we grow up.

Stem cells have two abilities: “differentiation” and “self-renewal.” “Differentiation” is an ability to develop into different types of cells making parts of a body, such as the skin and blood. “Self-renewal” is an ability to be divided into cells having the same ability as self, that is, a stem cell makes another stem cell.

What is a stem cell? Two abilities of stem cells

Analyses of the relationship between aging and stem cells have shown that the number of tissue stem cells in the bone marrow decreases with aging and, in people in their 80s, the number is only 1/200 of that in newborns. In other words, depletion of stem cells contributes to aging.

Relationship between aging and stem cells

Regenerative medicine and “Stem cells”

Nerves

Musclesand ligaments

Organs

Red blood cells

Bonesand cartilages

* Figure 1

Stem cell

Newborns Teens 30s 50s 80s0

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There are roughly 3 types of stem cells.

Somatic stem cells

Somatic stem cells are pluripotent stem cells that are present at various sites in our body. It was thought that these cells couldn’ t become any cells and had specific roles, for example,hematopoietic stem cells, which produce blood, become blood cells, and neural stem cells, which produce the nervous system, become nervous system cells. However, mesenchymal stem cells present in the bone marrow have been found to be so-called “multipotent” and differentiate to the muscles, cartilages, nerves, and others. That is, these cells are able to develop to different types of cells, like ES cells and IPS cells. Recent studies have shown that stem cells having properties similar to those of mes-enchymal stem cells present in the bone marrow are abundant in the subcuta-neous fat. These cells are called adipose-derived mesenchymal stem cells. Because they are easier to isolate than other tissue stem cells and adipose tissues are abundant, they draw attention as therapeutic cells.

Totipotent stem cell

The ability to develop into any type of cells is called “totipotency.” Only the fertilized egg cell has this ability for about 2 weeks immediately after fertil-ization and can become any type of cells, such as cells of a fetus or a pla-centa growing the fetus, as a source of life.

Pluripotent stem cells

ES is an abbreviation for “embryonic stem cell”. ES cells are stem cells made with inner cells of the embryo. The embryo is a mass consisting of about 100 cells developed from the fertilized egg by repeating cell division several times. ES cells are obtained by isolating cells inside this embryo and culturing them. ES cells have a potential to differentiate to any type of cells comprising our body and are expected to be applied to regenerative treatment and transplantation. Many research organizations are studying the application of ES cells. However, practical application is difficult because of the ethical issue associated with use of fertilized eggs.

The stem cell regenerative medicine treatment given atthis hospital uses these somatic stem cells.

Fertilized egg

IPS cellsES cells

Mesenchymalstem cell

Neuralstem cell

Epithelialstem cell

Hepaticstem cell

Vascularstem cell

Hematopoieticstem cell

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Target diseases of stem cell regenerative medicine treatment

Metabolic diseasesHyperlipidemiaRenal dysfunction Kidney diseases Gout Diabetes mellitusChronic renal failure

Immune diseasesAtopy Atopic dermatitis Alcohol-in-duced urticaria Allergic predisposition Sjogren’s syndrome Chemical sensitivity

Motor system injuriesLigament injury Muscle strain Lumbar spondylosis Lower back painCervical spinal stenosis Tuberculous caries

Cardiovascular diseasesAcute myocardial infarction Angina pectoris Hypertension Arrhythmia Atrial septal defectIdiopathic atrial fibrillation

Brain and nervous diseasesEthambutol optic neuropathy facial paralysis Cluster head-ache Dysautonomia Neurological sequelae Hearing loss Herniated disc Epilepsy Brainstem hemorrhage Brainstem hemorrhage sequelae Cerebral infarction Cerebral infarction sequelae Cerebral hemorrhage Brain tumor Tinnitus Spinal canal stenosis

OtherMenopauseSarcoidosisPostnatal depressionPeriodontal diseaseBedsore Prostatic hypertrophyMale menopauseHand joint pain Graves’ diseaseBehcet’s diseaseGlaucoma

Neurodegenerative diseasesAmyotrophic lateral sclerosis (ALS) Alzheimer’s disease Cerebral palsy Parkinson’s disease Chronic axonopathy

Respiratory diseasesChronic obstructive pulmonary disease (COPD) Bronchiectasis asthma Pulmonary suppuration Chronic renal failure

Malignant tumorsMalignant lymphoma Stomach cancer Liver cancer Pleural mesothelioma Esophageal cancer Prostate cancer Colon cancer Post-operative condition for ovarian cancer

Gastrointestinal diseasesLiver dysfunction Liver disease Liver dysfunction Reflux esophagitis Enteritis Constipation Chronic cholecystitisPancreaticobiliary maljunction

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(1) In surgical treatment, materials for transplantation, such as skin, cornea, cartilage, and heart muscle are made by inducing differentiation. Stem cells are trans-planted for bone marrow transplant and used to pro-duce red blood cells for transfusion. (Embryonic and somatic stem cells) (2) In medical treatment, stem cells are used for the treat-ment of acute diseases and external injuries. (Anti-in-flammatory action and growth factor action of stem cells) (3) Stem cells are used for prophylactic treatment and anti-aging. (DNA repair function) (4) Stem cells are used for the treatment of chronic dis-eases. (treatment of diseases by tissue repair function of somatic stem cells) (5) Stem cells are used to produce drugs. (Cytokines and growth factors produced by stem cells) (6) Stem cells are used for drug development (Cells for disease models produced by embryonic stem cells)

• My skin has become firm and resilient.• Gray hairs have turned black. Black hairs get

thicker.• I don’t get tired easily any longer.• I can sleep better.• My eyesight has recovered, and presbyopia has

improved.• Tension in the neck and shoulder has been

relieved.• I hardly catch a cold.• The intestinal condition and bowel movement

have improved.• Arrhythmia has improved.• Frequent urination has improved. I can finish uri-

nation more easily.• Erectile dysfunction (ED) has improved, result-

ing in more sexual desire.

What can stem cells do? Byproducts of treatment with stem cells: anti-aging effects

Potentials of medical treatmentbroadened by stem cells

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※ Age: 20 to 80 years old※ Patients diagnosed eligible for this therapy by a

physician of regenerative medicine

Treatment of diabetes mellitus with stem cells

In Japan and overseas countries, reports have now shown that stem cells have achieved various effects. Stem cell treat-ment is expected to restore function in patients with vascular or immune diseases or patients who failed to respond to existing treatment.

Treatment method

Target disease

Stem cells derived from the patient’ s own fat are administered to the patient with diabetes mellitus to improve symptoms by repair of pancreatic islet β cells, functional recovery, and suppression of inflammation. In this treatment, the fat-derived stem cells isolated from the patient’ s lypocyte are cultured until a required number of cells are obtained and then infused intravenously to the patient’s vein.

Diabetes mellitus•Patients with a history of hypersensitivity or allergic symptoms to an anesthetic used when fat is collected, or substances used during the production process of specific cell products•Patients with infection(A physician determines whether the treatment can be given to the patient on the basis of the patient’ s health condition and physical requirements.)

Not eligible for this therapy:

[Case] Male patient with diabetes mellitus in his 60s Administration of stem cells

Reference range (4.3-5.8)

Reference range (70-109)

5 years before

administration

4 years before

administration

3years before

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2 years before

administration

1 years before

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1 years after

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2 years after

administration

At present Start ofadministration

Hemoglobin A1c (%

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Blood glucose level(mg/dL)

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(1) After the patient’ s eligibility is confirmed, the physician who gives the treatment explains treatment to the patient with the informed consent form and patient infor-mation sheet, and answers questions from the patient. Then the patient is asked to provide informed consent in writing.

The physician who gives stem cell treatment determines the eligibility of patients for regenerative medicine by history taking and physical examination.

(2)Under local anesthesia, 5 to 10 mg of tissue is collected from the patient’ s lower abdomen.(3)A specific cell product necessary for treatment is produced from the lipocyte collected at a cell culture center approved by the Ministry of Health, Labour and Welfare.

Collection of tissue (cells)

(4)If no problem is found in the patient’ s condition during history taking, the physi-cian who gives regenerative medicine treatment determines whether the treatment can be performed.(5)The specific cell product is transplanted (administered) by intravenous infusion.

*Part of the specific cell product used is stored at −80 ° C or lower for 6 months, so that the cause can be investigated and identified if a disease or condition occurs.

Transplantation (administration) of specific cell product

(6) The patient who has received regenerative medicine treatment is asked to visit the hospital for follow-up periodically once per 30 days for 6 months from the day of receiving treatment. If the patient has difficulty to visit the hospital periodically, the patient may be asked to contact the physician periodically for follow-up at the dis-cretion of the physician.

Flow of treatment

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Flow of treatment

Patients

Coordinator in each district

Medical institutions belonging to JapanRegenerative Medicine Association

InquiryApplication Coordination

Contact

InquiryApplication

Treatment

Request/coordination based onthe association’s acceptance criteria

Notification of acceptance/rejection

Coordinator for this district:

Passage

Japan Regenerative MedicineAssociation(JRMA)