Research is ongoing in Japan and overseas with the aim of realizing cell transplantation therapy using iPS cells. One safety issue of concern is the risk of tumor formation. CiRA in particular has focused its resources on this issue.

Broadly speaking, there are two main theories as to the mechanism whereby iPS cells may form tumors. One theory is that iPS cells form tumors in response either to reactivation of the reprogramming factors inserted into the cell or through damage caused to the original cell genome through the artificial insertion of the reprogramming factors. In response, a search was launched for optimal reprogramming factors which do not cause reactivation, and a method of generating iPS cells was developed in which reprogramming factors are not incorporated into the cell chromosomes and damage to the host genome is therefore avoided.

The other theory is that residues of undifferentiated cells - cells which have not successfully completed differentiation to the target cell type - or other factors lead to the formation of teratomas, a kind of benign tumor. This theory requires research on iPS cell proliferation and differentiation.

1. Search for optimal reprogramming factorsWhen Professor Shinya Yamanaka and his research team announced the successful generation of mouse iPS cells, one of the reprogramming factors they used was c-Myc, which is known to be an oncogene, that is a cancer-causing gene. There have been suggestions that this gene may be activated within the cell and cause a tumor to form. However, in 2010, CiRA Lecturer Masato Nakagawa and his team reported that L-Myc was a promising replacement factor for c-Myc. iPS cells created using L-Myc not only display almost no tumor formation, they also have a high rate of successful generation and a high degree of pluripotency.

2. Search for optimal vectorsWhen the reprogramming factors required to generate iPS cells were inserted into the cells of the skin or other body tissues, early methods employed a retrovirus or lentivirus as a "vector," or carrier. In these methods, the target genes are inserted into the viruses with the which the cells were then infected in order to deliver the target genes. When a retrovirus or lentivirus is used as a vector, however, the viruses are incorporated into the cells genomic DNA in a random fashion. This may cause some of the cells original genes to be lost, or in other cases activated, resulting in a risk of cancerous changes.

In 2008, to remedy this risk, CiRA Lecturer Keisuke Okita and his team explored the use of a circular DNA fragment known as a plasmid, which is not incorporated into the cell chromosome, as a substitute to the retrovirus or lentivirus methods. In this way, they developed a method of generating iPS cells in which the reprogramming factors are not incorporated into the cell chromosome. In 2011, Okita and his team further improved the efficiency generation by introducing into a self-replicating episomal plasmid six factors - OCT3/4, SOX2, KLF4, LIN28, L-MYC, and p53shRNA.

3. Establishing a method for generating and screening safe cellsOnce iPS cells have been induced to differentiate into the target somatic cells using the appropriate genes and gene insertion methods as explained above, the differentiated cells can be relied upon not to revert to the undifferentiated state. However, there may sometimes be a residue of undifferentiated cells which have not completed the process of differentiation into the target cells, and it is possible that these cells, however few, may form a tumor. Scientists had already established that different iPS cell lines, even if generated from the same individual using the same method, might nevertheless display differences in proliferation and differentiation potentials. This meant that, if iPS cells with low differentiation potential were used, there was a risk that a residue of cells in the cell group might fail to fully differentiate and result in the formation of a teratoma. In 2013, a team led by CiRA Lecturer Kazutoshi Takahashi and Dr. Michiyo Aoi, now an assistant professor at Kobe University, developed a simple method to screen for iPS cell lines that have high potential to differentiate into nerve cells. There is also a risk of tumorigenesis from genomic or other damage arising at the iPS cell generation stage or at the subsequent culture stage. CiRA Assistant Professor Akira Watanabe and his team have developed a sensitive method to detect genomic and other damage in iPS cells using the latest equipment.

4. Developing a reliable method of differentiation into the target cell typeIn cell transplantation therapy, iPS cells are not transplanted directly into the human body. Instead, cells are transplanted after first being differentiated into the target cell type. It is therefore important to develop a reliable method of inducing iPS cells to differentiate into the target cell type. CiRA is currently working to develop technology for differentiation into a range of different cell types from iPS cells. CiRA Professor Jun Takahashi and his team have developed a highly efficient method of inducing iPS cells to differentiate into dopamine-producing nerve cells. In 2014, CiRA Professor Koji Eto and his team reported a method of producing platelets from iPS cells that is both reliable and can yield high volumes. These findings represent a major step toward iPS cell-based regenerative medicine for nerve diseases such as Parkinsons disease and blood diseases such as aplastic anemia.

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Much-anticipated human trial aiming to repair spinal cord damage about to begin  ABC News

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When the decision is made to have a stem cell or bone marrow transplant, there are several steps in theprocess. The steps are much the same, no matter what type of transplant youre going to have.

You will first be evaluated to find out if you are eligible for a transplant. A transplant is very hard on your body. For many people, transplants can mean a cure, but for some people, problems can lead to severe complications or even death. Youll want to weigh the benefits and risks before you start.

Transplants can also be hard emotionally. They often require being in the hospital, being isolated, and theres a high risk of side effects. Many of the effects are short-term, but some problems can go on for years. This can mean changes in the way you live your life. For some people its just for a while, but for others, the changes may be lifelong. Some of the side effects are really unpleasant and can be serious. Your cancer care team will do everything they can to make you comfortable, but some of the side effects may not be completely controlled or relieved.

Before you have a transplant, you need to discuss the transplant process and all its effects with your doctors. It also helps to talk with others who have already had transplants.

Its also very hard going through weeks and months of not knowing how your transplant will turn out. This takes a lot of time and emotional energy from the patient, caregivers, and loved ones. Its very important to have the support of those close to you. For example, youll need a responsible adult who will be with you to give you medicines, help watch for problems, and stay in touch with your transplant team after you go home. Your transplant team will help you and your caregiver learn what you need to know. The team can also help you and your loved ones work through the ups and downs as you prepare for and go through the transplant.

Many different medical tests will be done, and questions will be asked to try to find out how well you can handle the transplant process. These might include:

You will also talk about your health insurance coverage and related costs that you might have to pay.

You may have a central venous catheter (CVC) put into a large vein in your chest. This is most often done as outpatient surgery, and usually only local anesthesia is needed (the place where the catheter goes in is made numb). Nurses will use the catheter to draw blood and give you medicines.

If youre getting an autologous transplant, a special catheter can be placed that can also be used when your stem cells are being removed or harvested.

The CVC will stay in during your treatment and for some time afterward, usually until your transplanted stem cells have engrafted and your blood counts are on a steady climb to normal.

Younger people, people who are in the early stages of disease, or those who have not already had a lot of treatment, often do better with transplants. Some transplant centers set age limits. Some people also may not be eligible for transplant if they have other major health problems, such as serious heart, lung, liver, or kidney disease. A mini-transplant, described under Allogeneic stem cell transplant in Types of Stem Cell Transplants for Cancer Treatment may be an option for some of these people.

The hospitals transplant team will decide if you need to be in the hospital to have your transplant, if it will be done in an outpatient center, or if you will be in the hospital just for parts of it. If you have to be in the hospital, you will probably go in the day before pre-transplant chemo or radiation treatment begins (see the next section), the transplant team makes sure you and your family understand the process and want to go forward with it.

If you will be having all or part of your transplant as an outpatient, youll need to be very near the transplant center during the early stages. Youll need a family member or loved one to be a caregiver who can stay with you all the time. You and the caregiver will also need reliable transportation to and from the clinic. The transplant team will be watching you closely for complications, so expect to be at the clinic every day for a few weeks. You may still need to be in the hospital if your situation changes or if you start having complications.

To reduce the chance of infection during treatment, patients who are in the hospital are put in private rooms that have special air filters. The room may also have a protective barrier to separate it from other rooms and hallways. Some have an air pressure system that makes sure no unclean outside air gets into the room. If youre going to be treated as an outpatient, you will get instructions on avoiding infection. Usually, people who have transplants are in a separate, special part of the hospital to keep as many germs away as possible.

The transplant experience can be overwhelming. Your transplant team will be there to help you prepare for the process physically and emotionally and to discuss your needs. Every effort will be made to answer questions so you and your family fully understand what will be happening to you as you go through transplant.

Its important for you and your family to know what to expect, because once conditioning treatment begins (see the next section), theres no going back there can be serious problems if treatment is stopped at any time during transplant.

Having a transplant takes a serious commitment from you and your caregiver and family, so it is important to know exactly what to expect.

Conditioning, also known as pre-transplant treatment,bone marrow preparation, or myeloablation, is usually treatment with high-dose chemo and/or radiation therapy. Its the first step in the transplant process and typically takes a week or two. Its done for one or more of these reasons:

The conditioning treatment is different for every transplant. Your treatment will be planned based on the type of cancer you have, the type of transplant, and any chemo or radiation therapy youve had in the past.

If chemo is part of your treatment plan, it will be given in your central venous catheter and/or as pills. If radiation therapy is planned, its given to the entire body (called total body irradiation or TBI). TBI may be given in a single treatment session or in divided doses over a few days.

This phase of the transplant can be very uncomfortable because very high treatment doses are used. Chemo and radiation side effects can make you sick, and it may take you months to fully recover. A very common problem is mouth sores that will need to be treated with strong pain medicines. You may also have nausea, vomiting, be unable to eat, lose your hair, and have lung or breathing problems.

Conditioning can also cause premature menopause in women and often makes people sterile (unable to have children). (See Stem Cell Transplant Side Effects.)

After the conditioning treatment, youll be given a couple of days to rest before getting the stem cells. They will be given through your central venous catheter, much like a blood transfusion. If the stem cells were frozen, you might get some drugs before the stem cells are given. These drugs are used to help reduce your risk of reacting to the preservatives that are used when freezing the cells.

If the stem cells were frozen, they are thawed in warm water then given right away. There may be more than 1 bag of stem cells. For allogeneic or syngeneic transplants, the donor cells may be harvested (removed) in an operating room, and then processed in the lab right away. Once they are ready, the cells are brought in and given to you theyre not frozen. The length of time it takes to get all the stem cells depends on how much fluid the stem cells are in.

You will be awake for this process, and it doesnt hurt. This is a big step and often has great meaning for patientsand their families. Many people consider this their rebirth or chance at a second life. They may celebrate this day as they would their actual birthday.

Side effects from the infusion are rare and usually mild. The preserving agent used when freezing the stem cells causes many of the side effects. For instance, you might have a strong taste of garlic or creamed corn in your mouth. Sucking on candy or sipping flavored drinks during and after the infusion can help with the taste. Your body will also smell like this. The smell may bother those around you, but you might not even notice it. The smell, along with the taste, may last for a few days, but slowly fades away. Often having cut up oranges in the room will offset the odor. Patients who have transplants from cells that were not frozen do not have this problem because the cells are not mixed with the preserving agent.

Other side effects you might have during and right after the stem cell infusion include:

Again, side effects are rare and usually mild. If they do happen, they are treated as needed. The stem cell infusion must always be completed.

The recovery stage begins after the stem cell infusion. During this time, you and your family wait for the cells to engraft, or take, after which they start to multiply and make new blood cells. The time it takes to start seeing a steady return to normal blood counts varies depending on the patient and the transplant type, but its usually about 2 to 6 weeks. Youll be in the hospital or visit the transplant center daily for a number of weeks.

During the first couple of weeks youll have low numbers of red and white blood cells and platelets. Right after transplant, when your counts are the lowest, you may be given antibiotics to help keep you from getting infections. You may get a combination of anti-bacterial, anti-fungal, and anti-viral drugs. These are usually given until your white blood cell count reaches a certain level. Still, you can have problems, such as infection from too few white blood cells (neutropenia), or bleeding from too few platelets (thrombocytopenia). Many patients have high fevers and need IV antibiotics to treat serious infections. Transfusions of red blood cells and platelets are often needed until the bone marrow starts working and new blood cells are being made by the infused stem cells.

Except for graft-versus-host disease, which only happens with allogeneic transplants, the side effects from autologous, allogeneic, and syngeneic stem cell transplants are much the same. Problems may include stomach, heart, lung, liver, or kidney problems. (Stem Cell Transplant Side Effects goes into the details.) You might also go through feelings of distress, anxiety, depression, joy, or anger. Adjusting emotionally after the stem cells can be hard because of the length of time you feel ill and isolated from others.

You might feel as if you are on an emotional roller coaster during this time. Support and encouragement from family, friends, and the transplant team are very important to get you through the challenges after transplant.

The discharge process actually begins weeks before your transplant. It starts with the transplant team teaching you and your primary (main) caregiver about:

For the most part, transplant centers dont send patients home until they meet the following criteria:

(Why Are Stem Cell Transplants Used as Cancer Treatment? has more information about neutrophils, platelets, and hematocrit).

If you do not meet all of these requirements, but still dont need the intensive care of the transplant unit, you might be moved to another oncology unit. When you do go home, you might need to stay near the transplant center for some time, depending on your condition.

The process of stem cell transplant doesnt end when you go home. Youll feel tired, and some people have physical or mental health problems in the rehabilitation period. You might still be taking a lot of medicines. These ongoing needs must now be managed at home, so caregiver and friend/family support is very important.

Transplant patients are followed closely during rehab. You might need daily or weekly exams along with things like blood tests, and maybe other tests, too. During early rehab, you also might need blood and platelet transfusions, antibiotics, or other treatments. At first youll need to see your transplant team often, maybe even every day, but youll progress to less frequent visits if things are going well. It can take 6 to 12 months, or even longer, for blood counts to get close to normal and your immune system to work well. During this time, your team will still be closely watching you.

Some problems might show up as much as a year or more after the stem cells were infused. They can include:

Other problems can also come up, such as:

Your transplant team is still there to help you, even though the transplant happened months ago. Its important that you tell them about any problems you are having they can help you get the support you need to manage the changes that you are going through. They can also help you know if problems are serious, or a normal part of recovery. The National Bone Marrow Transplant Link helps patients, caregivers, and families by providing information and support services before, during, and after transplant. They can be reached at 1-800-LINK-BMT (1-800-546-5268) or online at http://www.nbmtlink.org.

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Acquisition of durable insulin-producing cells from human adipose tissue-derived mesenchymal stem cells as a foundation for cell- based therapy of diabetes mellitus  Nature.com

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1.5 Lakh Indians Register To Save Lives: Join the Mission To Fight Blood Cancer  The Better India

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AIIMS Bathinda Makes Breakthrough in Stem Cell Therapy Research for Heart Ailments  Elets

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New skin research could help slow signs of ageing  BBC.com

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Human skin map gives 'recipe' to build skin and could help prevent scarring  Medical Xpress

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Nobel Winner Shinya Yamanaka: Cell Therapy Is Very Promising For Cancer, Parkinsons, More  Forbes

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What are stem cells?

All of the blood cells in your body - white blood cells, red blood cells, and platelets - start out as young (immature) cells called hematopoietic stem cells. Hematopoietic means blood-forming.These are very young cells that are not fully developed. Even though they start out the same, these stem cells can mature into any type of blood cell, depending on what the body needs when each stem cell is developing.

Stem cells mostly live in the bone marrow (the spongy center of certain bones). This is where they divide to make new blood cells. Once blood cells mature, they leave the bone marrow and enter the bloodstream. A small number of the immature stem cells also get into the bloodstream. These are called peripheral blood stem cells.

Stem cells make red blood cells, white blood cells, and platelets. We need all of these types of blood cells to keep us alive. For these blood cells to do their jobs, you need to have enough of each of them in your blood.

Red blood cells carry oxygen away from the lungs to all of the cells in the body. They bring carbon dioxide from the cells back to the lungs to be exhaled. A blood test called a hematocrit shows how much of your blood is made up of RBCs. The normal range is about 35% to 50% for adults. People whose hematocrit is below this level have anemia. This can make them look pale and feel weak, tired, and short of breath.

White blood cells help fight infections caused by bacteria, viruses, and fungi. There are different types of WBCs.

Neutrophilsare the most important type in fighting infections. They are the first cells to respond to an injury or when germs enter the body. When they are low, you have a higher risk of infection. The absolute neutrophil count (ANC) is a measure of the number of neutrophils in your blood. When your ANC drops below a certain level, you have neutropenia. The lower the ANC, the greater the risk for infection.

Lymphocytesare another type of white blood cell. There are different kinds of lymphocytes, such as T lymphocytes (T cells), B lymphocytes (B cells), and natural killer (NK) cells. Some lymphocytes make antibodies to help fight infections. The body depends on lymphocytes to recognize its own cells and reject cells that dont belong in the body, such as invading germs or cells that are transplanted from someone else.

Platelets are pieces of cells that seal damaged blood vessels and help blood to clot, both of which are important in stopping bleeding. A normal platelet count is usually between 150,000/cubic mm and 450,000/cubic mm, depending on the lab that does the test. A person whose platelet count drops below normal is said to have thrombocytopenia, and may bruise more easily, bleed longer, and have nosebleeds or bleeding gums. Spontaneous bleeding (bleeding with no known injury) can happen if a persons platelet count drops lower than 20,000/mm3. This can be dangerous if bleeding occurs in the brain, or if blood begins to leak into the intestines or stomach.

You can get more information on blood counts and what the numbers mean in Understanding Your Lab Test Results.

Depending on the type of transplant thats being done, there are 3 possible sources of stem cells to use for transplants:

Bone marrow is the spongy liquid tissue in the center of some bones. It has a rich supply of stem cells, and its main job is to make blood cells that circulate in your body. The bones of the pelvis (hip) have the most marrow and contain large numbers of stem cells. For this reason, cells from the pelvic bone are used most often for a bone marrow transplant. Enough marrow must be removed to collect a large number of healthy stem cells.

The bone marrow is harvested (removed) while the donor is under general anesthesia (drugs are used to put the patient into a deep sleep so they dont feel pain). A large needle is put through the skin on the lower back and into the back of the hip bone. The thick liquid marrow is pulled out through the needle. This is repeated until enough marrow has been taken out. (For more on this, see Whats It Like to Donate Stem Cells?)

The harvested marrow is filtered, stored in a special solution in bags, and then frozen. When the marrow is to be used, its thawed and then put into the patients blood through a vein, just like a blood transfusion. The stem cells travel to the bone marrow, where they engraft or take and start to make blood cells. Signs of the new blood cells usually can be measured in the patients blood tests in a few weeks.

Normally, not many stem cells are found in the blood. But giving stem cell donors shots of hormone-like substances called growth factors a few days before the harvest makes their stem cells grow faster and move from the bone marrow into the blood.

For a peripheral blood stem cell transplant, the stem cells are taken from blood. A special thin flexible tube (called a catheter) is put into a large vein in the donor and attached to tubing that carries the blood to a special machine. The machine separates the stem cells from the rest of the blood, which is returned to the donor during the same procedure. This takes several hours, and may need to be repeated for a few days to get enough stem cells. The stem cells are filtered, stored in bags, and frozen until the patient is ready for them. (For more on this, see Whats It Like to Donate Stem Cells?)

When theyre given to the patient, the stem cells are put into a vein, much like a blood transfusion. The stem cells travel to the bone marrow, engraft, and then start making new, normal blood cells. The new cells are usually found in the patients blood in about 4 weeks.

The blood of newborn babies normally has large numbers of stem cells. After birth, the blood thats left behind in the placenta and umbilical cord (known as cord blood) can be taken and stored for later use in a stem cell transplant. Cord blood can be frozen until needed. A cord blood transplant uses blood that normally is thrown out after a baby is born. After the baby is born, specially trained members of the health care team make sure the cord blood is carefully collected. The baby is not harmed in any way. More information on donating cord blood can be found in Whats It Like to Donate Stem Cells?

Even though the blood of newborns has large numbers of stem cells, cord blood is only a small part of that number. So, a possible drawback of cord blood is the smaller number of stem cells in it. But this is partly balanced by the fact that each cord blood stem cell can form more blood cells than a stem cell from adult bone marrow. Still, cord blood transplants can take longer to take hold and start working. Cord blood is given into the patients blood just like a blood transfusion.

Some cancers start in the bone marrow and others can spread to it. Cancer attacks the bone marrow, causing it to make too many of some cells that crowd out others, or causing it to make cells that arent healthy and don't work like they should. For these cancers to stop growing, they need bone marrow cells to work properly and start making new, healthy cells.

Most of the cancers that affect bone marrow function are leukemias, multiple myeloma, and lymphomas. All of these cancers start in blood cells. Other cancers can spread to the bone marrow, which can affect how blood cells function, too.

For certain types of leukemia, lymphoma, and multiple myeloma, a stem cell transplant can be an important part of treatment. The goal of the transplant is to wipe out the cancer cells and the damaged or non-healthy cells that aren't working right, and give the patient new, healthy stem cells to start over."

Stem cell transplants are used to replace bone marrow cells that havebeen destroyed by cancer or destroyed by the chemo and/or radiation used to treat the cancer.

There are different kinds of stem cell transplants. They all use very high doses of chemo (sometimes along with radiation) to kill cancer cells. But the high doses can also kill all the stem cells a person has and can cause the bone marrow to completely stop making blood cells for a period of time. In other words, all of a person's original stem cells are destroyed on purpose. But since our bodies need blood cellsto function, this is where stem cell transplants come in. The transplanted stem cells help to "rescue" the bone marrow by replacingthe bodys stem cells that have been destroyedby treatment. So, transplanting the healthy cellslets doctors use much higher doses of chemo to try to kill all of the cancer cells, and the transplanted stem cells can grow into healthy, mature blood cells that work normally and reproduce cells that are free of cancer.

There's another way astem cell transplant can work, if it's a transplant that uses stem cells from another person (not the cancer patient). In these cases, the transplant can help treat certain types of cancer in a way other than just replacing stem cells. Donated cells can often find and kill cancer cells better than the immune cells of the person who had the cancer ever could. This is called the graft-versus-cancer or graft-versus-leukemia effect. The "graft" is the donated cells. The effect means that certain kinds of transplants actually help kill off the cancer cells, along with rescuing bone marrow and allowing normal blood cells to develop from the stem cells.

Although a stem cell transplant can help some patients, even giving some people a chance for a cure, the decision to have a transplant isnt easy. Like everything in your medical care, you need to be the one who makes the final choice about whether or not youll have a stem cell transplant. Transplant has been used to cure thousands of people with otherwise deadly cancers. Still, there arepossible risks and complications that can threaten life, too. People have died from complications of stem cell transplant. The expected risks and benefits must be weighed carefully before transplant.

Your cancer care team will compare the risks linked with the cancer itself to the risks of the transplant. They may also talk to you about other treatment options or clinical trials. The stage of the cancer, patients age, time from diagnosis to transplant, donor type, and the patients overall health are all part of weighing the pros and cons before making this decision.

Here are some questions you might want to ask. For some of these, you may need to talk to the transplant team or the people who work with insurance and payments for the doctors office and/or the hospital:

Be sure to express all your concerns and get answers you understand. Make sure the team knows whats important to you, too. Transplant is a complicated process. Find out as much as you can and plan ahead before you start.

Its important to know the success rate of the planned transplant based on your diagnosis and stage in treatment, along with any other conditions that might affect you and your transplant. In general, transplants tend to work better if theyre done in early stages of disease or when youre in remission, when your overall health is good. Ask about these factors and how they affect the expected outcomes of your transplant or other treatment.

Many people get a second opinion before they decide to have a stem cell transplant. You may want to talk to your doctor about this, too. Also, call your health insurance company to ask if they will pay for a second opinion before you go. You might also want to talk with them about your possible transplant, and ask which transplant centers are covered by your insurance.

Stem cell transplants cost a lot, and some types cost more than others. For example, getting a donor's cells costs more than collecting your own cells. And, different drug and radiation treatments used to destroy bone marrow can have high costs. Some transplants require more time in the hospital than others, and this can affect cost. Even though there are differences, stem cell transplants can cost hundreds of thousands of dollars.

A transplant (or certain types of transplants) is still considered experimental for some types of cancer, especially some solid tumor cancers, so insurers might not cover the cost.

No matter what illness you have, its important to find out what your insurer will cover before deciding on a transplant, including donor match testing, cell collection, drug treatments, hospital stay, and follow-up care. Go over your transplant plan with them to find out whats covered. Ask if the doctors and transplant team you plan to use are in their network, and how reimbursement will work. Some larger insurance companies have transplant case managers. If not, you might ask to speak with a patient advocate. You can also talk with financial or insurance specialists at your doctors office, transplant center, and hospital about what expenses you are likely to have. This will help you get an idea of what you might have to pay in co-pays and/or co-insurance.

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A stem cell transplant (also known as a bone marrow transplant) is a procedure in which defective or cancerous bone marrow is replaced with new, healthy bone marrow cells. A stem cell transplant may be used to treat leukemia and lymphoma, cancers that affect the blood and lymphatic system. Additionally, transplants are used to treat hereditary blood disorders, such as sickle cell anemia, and autoimmune diseases, such as multiple sclerosis. They also can help patients recover from or better tolerate cancer treatment.

Stem cells are specialized cells that can mature into different kinds of cells, depending on what your body needs. They are located in various places throughout your body, including your bone marrow. Bone marrow contains hematopoietic stem cells that constantly divide to produce all the different kinds of blood cells. Young hematopoietic stem cells can mature into any of the following cell types:

Any disease or condition that impacts the ability of your bone marrow to produce new blood cells can have serious health consequences. Bone marrow transplantation may be an effective treatment for such conditions.

In general, the first step to a successful stem cell transplant is harvesting healthy bone marrow, either from the patient or from a donor. This involves putting the patient or donor under general anesthesia and using a large needle to remove bone marrow from their pelvis. The bone marrow can then be frozen and stored. When it is ready for use, it is thawed and injected into a patient, much like a blood transfusion. The healthy stem cells will travel to bone marrow sites and start making blood cells.

There are two types of stem cell transplantation:

In an autologous stem cell or bone marrow transplant, healthy cells are harvested from the bone marrow of a patient. The harvested bone marrow is frozen and stored until it is ready for use. In the meantime, the patient undergoes a 'conditioning regimen' to prepare their body for the transplant. In this regimen, they may receive high dose chemotherapy r radiation therapy. These treatments destroy cancer cells, but they also kill bone marrow cells. This is where the transplant comes in. The patient is injected with their own stored blood stem cells. These cells 'take' to the body and restore its ability to produce blood cells.

Autologous transplantation is most often used to treat diseases like lymphoma and multiple myeloma. Because autologous transplants use the cells of a patient, they have little to no risk of rejection or graft-versus-host disease (GVHD).This makes it safer than allogeneic transplants.

An allogeneic bone marrow or stem cell transplant uses donor stem cells to treat blood cancers that affect the bone marrow, like leukemia. The cell transplants come from a donor whose tissue most closely matches that patient. The donor cells are injected after the patient has undergone chemotherapy. But beyond restoring the blood-producing ability of the body, allogeneic stem cell transplantation can help fight cancer directly. The donated cells generate a new immune response, meaning they find and kill cancer cells, sometimes better than the original immune cells of the patient. This is called the graft-versus-cancer effect, and it can help fight cancer. Unfortunately, allogeneic stem cells come with an increased risk of rejection or GVHD.

For allogeneic transplants to work, a patient needs to be matched with a donor whose human leukocyte antigen (HLA) proteins closely match theirs. HLA proteins dot your cells' surface and help your body distinguish normal cells from foreign cells. If the HLA proteins of a donor are a poor match to a patient, there is an increased risk of GVHD.

HLA typing is the process by which stem cell transplant patients are matched with eligible donors. In HLA typing, a blood sample from a patient is compared with samples from family members or a donor registry. The best match is usually a first-degree relative (children, siblings, or parents). However, about 75% of patients do not have suitable donors in their family and require cells from a matched unrelated donor (MUD). Stem cell donors are located through registries such as the National Marrow Donor Program. It can sometimes take several weeks or longer to find a suitable donor.

If a suitable donor cannot be found, there are other options, including:

Before the transplant, your doctors will need to prepare your body to receive the new stem cells. This is called the preparative or conditioning regimen. It consists of chemotherapy and radiation given several days before your transplant.Stem cell transplant side effects can be caused by the preparative regimen or by the transplant itself.Your transplant team can help you cope with side effects. Some can be prevented, and most can be treated to help you feel better.

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Stem Cell (Bone Marrow) Transplants - MD Anderson Cancer Center

Bone Marrow Stem Cells Comments Off on Stem Cell (Bone Marrow) Transplants – MD Anderson Cancer Center | October 13th, 2024

Imagine finding out that your bone marrow or blood stem cells could save the life of someone who needed it even a complete stranger. Memorial Sloan Kettering Cancer Center (MSK) nurse Grace Yang, RN, received such a call in March 2024.

This is definitely something I was never expecting to happen to me, Yang says. But because I work in the Bone Marrow Transplant [BMT] Service, I knew the impact it could have on somebody elses life. It felt like a privilege to be able to help in a different way. Yang works as an office practice nurse for BMT and cellular therapy specialist Heather Landau, MD.

Stem cell and bone marrow donations can offer people with blood cancer and other blood diseases the best chance for a cure. There is an urgent need for more donors between the ages of 18 and 40, especially donors of non-European and mixed ancestry. Yang, who is of Asian ancestry, was 29 when she donated.

You may wonder how to donate, whether donating bone marrow or blood stem cells is painful, and whats involved in bone marrow and stem cell transplantation procedures. Heres what you need to know.

First, some background: Transplanting donor stem cells that form new blood cells in a patient is a lifesaving treatment for many people with blood cancers like leukemia and lymphoma,as well as some other blood diseases. Contrary to what many people might think, the cells used in the transplant are usually collected from the donors bloodstream. Only on rare occasions are the stem cells taken from the bone marrow.

These donor cells are needed because before receiving a transplant, patients are given chemotherapyand sometimes radiationto wipe out the cancer. These treatments also destroy the patients blood-making cells.So they need healthy blood stem cells to be infused into their body. This transplant procedure enables patients to grow new blood cells and recover from the treatment.

Every year, about 18,000 people in the United States are diagnosed with a life-threatening illness for which a stem cell transplant from a donor is the best treatment option. Unfortunately, only about 30% of those patients have a family member who is the best match. That means that about 12,000 people need to find an unrelated donor.

One way that donors are found is through NMDP, which maintains a registry for connecting unrelatedvolunteer donorswith patientsin need. Unfortunately, many people are reluctant to join this registrybecause they dont realize the process is easier than they think, nor do they fully appreciate the desperate need for donors.

Yang signed up for the NMDP registry through a community drive, before she even worked in the BMT field. More than a decade later, she learned she was a match with a patient. I encourage all the people around me to sign up, she says. They are shocked that its so easy.

Even if a patient has an adult sibling who is the right age to donate, there is only a 1 in 4 chance a sibling will be a perfect match.

Siblings and other family members are often a half match, and this can be a good option for many patients. But for some patients, the best way to maximize the chances of a successful transplant is to find a fully matched donor even one who is unrelated.

There are a lot of misconceptions about donating bone marrow and stem cells, especially that it is a burden or painful.

When Yang first told her parents that she had been matched to a patient in need, she found out that her father had also donated bone marrow to stranger more than 20 years ago. At that time, the process was more complicated. Because of his past experience, her father was a bit concerned about what she might go through, but she explained that thanks to advances in technology, the donation process is much easier than it used to be.

Here is a step-by-step guide:

Because studies have shown that patients receiving blood stem cells from younger donors have a better long-term survival rate, you must be between the ages of 18 and 40 to join the registry.

Joining the registry is simple. Go to http://www.bethematch.org to order a collection test kit that will be sent to your house. The website may also direct you to a local registration drive in your area. Once you get the kit, all you need to do is wipe a cotton swab on the inside of your cheek, seal it in a provided container, and mail it back.

You will be contacted if you are a full match or a partial match for a patient in need of a bone marrow or stem cell transplant. Congratulations! Your cells may be the best option to save that persons life.

Several additional steps will be needed to confirm that a transplant with your cells is likely to be successful. These include filling out a health questionnaire, having additional blood tests, and undergoing a physical examination.

If testing confirms that you are a suitable donor, your donation will be scheduled for a time that works for you and for the patients treatment schedule. Depending on where you live, you may need to travel to one of the specialized facilities that collects the stem cells from blood or bone marrow. If you need to travel, your expenses will be covered by NMDP.

Yang traveled to Chicago to make her donation, and the NMDP not only arranged her trip and paid for everything, but it also paid for her sister to travel with her so she didnt have to go alone.

Thanks to procedures developed over the past few decades, 90% of the time the stem cells needed for the transplant are taken from the blood, not the bone marrow. This process is much easier for donors because it does not require surgery.

With stemcell donation from the blood, there is little pain. It is very similar to donating blood platelets. The main difference is that for a few days ahead of time, donors need to receive an injection of a drug called filgrastim (Neupogen), which stimulates the bone marrow to produce extra blood-forming stem cells. Donors may experience some bone pain or a low-grade fever while taking filgrastim, but the side effects usually are not severe and go away after the donation process is complete.

Most people are able to give themselves injections of filgrastim at home, so they dont need to go to the doctor every day.

On the day of the donation, the donor is hooked up to what is called an apheresis machine. The blood is collected from one arm, sent through a machine that removes the stem cells, and then returned to the other arm. Other than the initial needle prick, it is not a painful experience.

The process takes several hours, during which donors often read or watch movies. It may be necessary for donors to return for a second day, depending on how many cells are retrieved.

For Yang, the donation took about 3 hours. We started in the morning, and I was done before lunch, she says. The nurses did a great job of making me feel comfortable and checked on me often throughout the process.

In only about 10% of cases, doctors may recommend the patient receive a bone marrow donation requiring a surgical procedure. Donors are placed under general anesthesia, while bone marrow is removed from small holes drilled into their pelvic bones.

This procedure takes an hour or two, and usually donors can go home that same day.

If you have donated stem cells from your blood, you may feel tired for a few days, but many donors feel no effects at all the next day.

If you have donated bone marrow, you will probably have some pelvic and hip pain, as well as some bruising, for a few days after the procedure. These aches and pains can be controlled with over-the-counter pain medications like Advil and Tylenol. Most people can go back to regular activities right away, but your medical team can provide more details for specific activities.

The process by which the donor and recipient are matched is called HLA (human leukocyte antigen) typing. Its not the same as blood type.Instead, it has to do with the immune proteins that we all inherit at birth from both of our parents. The immune system uses these proteins to understand which cells belong to your body and which do not. A perfect match means that 8 out of 8 markers are the same.

Matching is not related to gender, so your donation can go to someone of any gender as long as the HLA markers align.

Yang has not yet learned anything about the patient who received her cells, but hopes to in the coming months. I just feel so lucky that I was able to do something amazing for somebody else, she says.

Not everyone who needs a donor is able to find one who is fully matched. A patients best chance of finding a donor is someone within their own ethnic group. Members of certain ethnic groups, including those of Latin American, Asian, African, and Middle Eastern ancestry, have a harder time finding a match. These groups tend to be underrepresented in public registries.

For example, for people of Latin American descent, the odds of finding a matched donor in a public registry are less than 50%. For Black patients, the odds are only about 30%. It may be even harder for people of mixed ethnic backgrounds to find donors because their HLA makeup can be more complex.

This makes it especially important for people from these underrepresented ethnic groups, as well as those who have mixed ancestry, to join a public registry like NMDP.

For patients who are unable to find a fully matched donor, there are other options. These include:

These treatments can offer patients very good outcomes, but in some cases its better to have a donor who is a perfect match.

Yang says even though she works as a BMT nurse, she still had questions throughout the donation process. Everyone at NMDP is great about addressing any concerns you may have about the process, and they have many great resources, she says. Any time I have the opportunity to talk to someone about this, I encourage them to get involved.

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Donating Bone Marrow and Stem Cells: The Process and What To Expect

Bone Marrow Stem Cells Comments Off on Donating Bone Marrow and Stem Cells: The Process and What To Expect | October 13th, 2024

Diseases like leukemia, lymphoma, multiple myeloma or bone marrow failure syndromes can affect bone marrow. Bone marrow is a spongy tissue inside bones that is rich in stem cells and helps to produce blood and immune cells. Healthy stem cells are often needed to treat these marrow-impacting diseases. This is why stem cell transplant and bone marrow transplant are often used interchangeably, the main difference being the method of collection of the stem cells.

In some cases especially for some blood cancers a person can use stem cells from their own body to facilitate giving higher doses of chemotherapy in an attempt to cure the disease. This is called an autologous stem cell transplant. The other option, especially when a recipients bone marrow is already compromised, requires a donor to provide healthy stem cells, which is called an allogeneic stem cell transplant.

William Hogan, M.B., B.Ch., is a consultant hematologist and director of the Mayo Clinic Blood and Bone Marrow Transplant Program. Dr. Hogan says that about one-quarter of transplant recipients at Mayo Clinic receive an allogeneic transplant, which means a donors immune system is used in a life-sustaining and curative therapy to help eradicate disease.

If you are selected (as a bone marrow donor), you might be a critically important part of a persons treatment, he says.

To help someone with an allogenic stem cell transplant, you can donate stem cells from your:

Health care providers determine which type of donation is best for a person on a case-by-case basis. Factors that influence this decision can include the type of disease, the degree of donor matching, and other patient characteristics like age and remission status.

Dr. Hogan says that in the past, family members especially fully matched siblings were considered the best option to donate bone marrow. But the fact is that a majority of people who need a bone marrow transplant dont have a family member who is a full match.

Additionally, cancers that require bone marrow transplants frequently affect older adults. Older adult sibling donors are more likely to have co-morbidities that can put the donor at risk and can increase the risk of complications with the recipient.

For these reasons, the National Marrow Donor Program manages a registry of bone marrow donors that can be matched with unrelated recipients.

To help increase the long-term survival rate of a bone marrow recipient, the National Marrow Donor Program prefers healthy donors who are 18 to 35 years old, although Dr. Hogan says that older donors can be an option in select circumstances. He says that determining a good match for a bone marrow transplant includes looking at a donors proteins in cells called human leukocyte antigens (HLA) and blood type. Optimal donors will match HLA and blood type and be free of genetic and infectious diseases.

Being a donor does require a time commitment, often 20 to 30 hours over 4 to 6 weeks from screening to donation. In terms of financial requirements to be a bone marrow donor through the National Marrow Donor Program, there arent any. All your medical and travel expenses are covered.

The U.S. Health Resources & Services Administration states that even though there are more than 40 million potential bone marrow donors in the world, its harder for people with racially and ethnically diverse backgrounds to find a match.

Getting greater diversity in the bone marrow registry is important, since ethnicity impacts HLA matching to some degree, says Dr. Hogan. We need to ensure that underrepresented minorities have adequate representation. We want to provide better donors for better outcomes.

According to the National Marrow Donor Program, people who need bone marrow are most likely to match with someone of their own ethnic background. The odds of finding a match through the bone marrow donation registry vary based on ethnic background. For example, if a recipient is white, they have a 79% chance of finding a match. If they are Hispanic or Latino, the odds of a match drop to 48%. And for recipients who are Black or African American, the chance of finding a match is just 29%.

If you donate bone marrow, you will undergo surgery. During the surgery, you are under general anesthesia and a needle is inserted into your hip bones to collect the bone marrow. The effects of general anesthesia can include more minor complaints such as a sore throat and nausea, as well as some serious but rare complications.

Aside from the use of anesthesia, other risks of bone marrow donation surgery include:

After the surgery to collect bone marrow, you might experience pain where the needle was inserted when you bend or walk. The pain tends to lessen after the first several days and is usually gone within 6 to 12 weeks.

Dr. Hogan says that there are misconceptions about the pain associated with bone marrow donation. Many donors report that the value of their donation and the contribution to saving somebodys life often outweighs the discomfort of the procedure, he says.

He explains that donation surgery is more involved than a blood draw, but the pain should be well managed, and most donors have a positive experience.

Many people take several days off following bone marrow collection surgery so that they can take rest periods throughout the day and slowly resume normal activities. After the collection, it takes a few weeks for your bone marrow to replenish, and after that, most symptoms like soreness and fatigue should be gone. The total recovery process can typically take 2 to 6 weeks, according to Dr. Hogan.

If you are highly motivated to help others, Dr. Hogan suggests that you start at the National Marrow Donor Programs Be the Match site, where you can learn more about the process to join and what happens if you are selected as a match.

Joining the voluntary registry is a simple process. First, youll answer questions about your medical history in an initial screening. If you qualify, the next step is to swab the inside of your cheek to determine your HLA type. Those two steps are what it takes to join.

Once youve joined the registry, you might not be identified as a match until you opt out or age out when you turn 61. Once youve joined the registry, you can change your mind about being a donor at any time.

Even if you join the registry with the intent of helping a friend or family member, it might turn out that youre a better match for someone you dont know. If you do match, you might be asked to donate either bone marrow or blood, depending on what the recipient needs.

If you are selected as a match, your donation has the power to transform someones life.

Relevant reading

Mayo Clinic The Integrative Guide to Good Health

As Americans seek greater control of their health, explosive growth is taking place in the field of integrative medicine. More and more, people are looking for more natural or holistic ways to maintain good health; they want not only to manage and prevent illness but also to improve their quality

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What to expect as a stem cell or bone marrow donor

Bone Marrow Stem Cells Comments Off on What to expect as a stem cell or bone marrow donor | October 13th, 2024

Curr Opin Hematol. Author manuscript; available in PMC 2022 Jan 1.

Published in final edited form as:

PMCID: PMC7769132

NIHMSID: NIHMS1651634

1.Division of Experimental Hematology and Cancer Biology, Cincinnati Childrens Medical center, Cincinnati, Ohio, 25228, USA

2.Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45229, USA

1.Division of Experimental Hematology and Cancer Biology, Cincinnati Childrens Medical center, Cincinnati, Ohio, 25228, USA

2.Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45229, USA

The bone marrow is the main site for hematopoiesis. It contains a unique microenvironment that provides niches that support self-renewal and differentiation of hematopoietic stem cells (HSC), multipotent progenitors (MPP), and lineage committed progenitors to produce the large number of blood cells required to sustain life. The bone marrow is notoriously difficult to image; because of this the anatomy of blood cell production- and how local signals spatially organize hematopoiesis-are not well defined. Here we review our current understanding of the spatial organization of the mouse bone marrow with a special focus in recent advances that are transforming our understanding of this tissue.

Imaging studies of HSC and their interaction with candidate niches have relied on ex vivo imaging of fixed tissue. Two recent manuscripts demonstrating live imaging of subsets of HSC in unperturbed bone marrow have revealed unexpected HSC behavior and open the door to examine HSC regulation, in situ, over time. We also discuss recent findings showing that the bone marrow contains distinct microenvironments, spatially organized, that regulate unique aspects of hematopoiesis.

Defining the spatial architecture of hematopoiesis in the bone marrow is indispensable to understand how this tissue ensures stepwise, balanced, differentiation to meet organism demand; for deciphering alterations to hematopoiesis during disease; and for designing organ systems for blood cell production ex vivo.

Keywords: Hematopoiesis, bone marrow organization and architecture, hematopoietic stem cell niches, hematopoietic progenitor niches, bone marrow microenvironment

Hematopoiesis takes place in the bone marrow (BM) where hematopoietic stem cells and multipotent progenitors (HSPC) self-renew and progressively differentiate into lineage-specific, unipotent, progenitors responsible for production of each major blood lineage. The bone marrow has been studied in detail using multiple approaches including scRNAseq, and in vivo lineage tracing studies [19]. These and other studies have dramatically changed our understanding of how the different stem and progenitor populations differentiate, and how they are regulated by the BM microenvironment- the collection of hematopoietic and stromal cells and structures that supports differentiation- during normal and stress hematopoiesis. Our understanding of the spatial organization of hematopoiesis in the bone marrow is less comprehensive. Spatial analyses of differentiating progenitors, their offspring, and the supporting microenvironment are challenging due to several factors (reviewed in [10]); a) the bone marrow is fully enclosed by opaque bone which makes direct observation difficult and requires extensive preparation steps in order to generate high quality samples for imaging analyses; b) the hematology field has used increasingly complex combinations of cell surface markers -requiring simultaneous detection upwards of 15 antibodies- to define each hematopoietic progenitor and mature cell in the bone marrow. In contrast fluorescent analyses are generally limited to much fewer (4-7) parameters preventing simultaneous identification of multiple cell types. Further, many antibodies used to define cells by flow cytometry fail to detect the same cells in imaging analyses, either because the signals are too dim or because sample preparation destroyed the epitopes recognized by that antibody; c) scRNAseq analyses of stromal cells in the bone marrow have revealed extraordinary complexity [79**]. However, there are no validated antibodies to detect many of these stromal populations and the field relies in Cre/fluorescent reporter mice that identify some stromal components but fail to completely resolve the different populations [11]; d) the bone marrow contains large numbers of mature cells but stem cells and progenitors are exceedingly rare. This makes identification of sufficient numbers of HSPC for adequately powered statistical analyses very challenging and time consuming; e) different groups have used different statistical approaches and methods to define proximity of cells to structures and a global consensus on which approaches to use has yet to emerge. Despite numerous challenges the field has made tremendous progress in defining the architecture of the BM and deciphering how local cues from the microenvironment regulate stem and progenitor cells. Here we summarize our current understanding of the spatial organization of the bone marrow, its impact on hematopoiesis, and discuss recent discoveries that are transforming the field.

The main structures that spatially organize the bone marrow are the bone, the vasculature, and a network of reticular stromal cells. The bone completely encloses the bone marrow, defines its boundaries, and projects trabeculae that penetrate into the BM parenchyma (). The bone marrow vasculature is composed of rare arterioles that enter through the bone and transform into transitional vessels that give rise to an extremely dense network of fenestrated sinusoids that occupy most of the BM space (). The vasculature is tightly associated with a network of perivascular reticular cells that spreads through the BM. Hematopoiesis takes place in the spaces between vessels, bone, and reticular cells (). Many other types of stromal (non-hematopoietic) cells are present in the bone marrow including sympathetic nerves, Schwann cells, adipocytes, osteoblasts, osteocytes, osteoblastic precursors, and diverse types of fibroblasts. These are reviewed elsewhere [1214]. These cells and structures in association with different types of hematopoietic cells-cooperate to provide distinct microenvironments that regulate and regionally organize-hematopoiesis in the bone marrow.

Schematic representation of the spatial organization of the mouse bone marrow under homeostasis. The endosteum, the vasculature and a network of reticular stromal cells define the volumes available for hematopoiesis. vWF+ HSC reside in a sinusoidal/megakaryocytic/reticular niche far from arterioles and the endosteum while vWF- reside in an arteriolar niche enriched in Ng2+ cells [38]. Note that this arteriolar niche also contains sinusoids and reticular cells. HSC in the central BM constantly traffic between reticular cells [27**]. Subsets of HSC -reserve HSC [33*] and MFG-HSC [26] localize to endosteal regions where they proliferate in response to stress, likely in areas undergoing simultaneous bone deposition by osteoblasts and bone resorption by osteoclasts [26]. GMP are distributed through the BM but form clusters in respond to stress [50]. Lymphoid progenitors have been mapped to the endosteum [18] but also to different types of reticular cells [42,60]. Erythropoiesis takes place in erythroblastic islands presumably adjacent to the same sinusoids that support erythroid progenitors [61,62,64*].

The best studied microenvironments in the bone marrow are the hematopoietic stem cell niches, which are responsible for ensuring that HSC are maintained through the life of the organism. The discovery of a two color strategy (LinCD48CD41CD150+) to detect HSC using confocal microscopy [15] led to an explosion of studies that used imaging to identify candidate HSC niche components that were later validated using complementary approaches [1522]. These analyses have been further refined by the development of mouse fluorescent reporter lines that identify populations highly enriched in HSC [2327**]. These studies showed that in the steady-state- HSC are always found as single cells and adjacent to perivascular cells and sinusoids. Most HSC exclusively localize to sinusoids but smaller fractions localize to areas that also contain arterioles and endosteal surfaces. Cells associated with each of these structures produce cytokines and growth factors that regulate HSC self-renewal and function (). The precise components of HSC niches and how they regulate HSC have been reviewed in detail elsewhere [13,28,29]. Here we will highlight recent insights from live imaging analyses of HSC.

Until recently live imaging of HSC in the bone marrow was restricted to experiments were HSC were prospectively isolated, transferred into recipient mice, and then imaged [30]. This has changed with the development of live imaging approaches of unperturbed HSC. Christodoulou et al., [26**] used Mds1GFP+, and Mds1GFP/+Flt3-Cre mice. In Mds1GFP+ mice the Mds1 promoter drives GFP expression in HSC and multipotent progenitors. However, in the Mds1GFP/+Flt3-Cre mice, Cre expression results in excision of the GFP cassette in all cells except a small (12%) subset of quiescent LT-HSC (MFG-HSC). Using live imaging of the calvarium they found that both the Mds1GFP+ HSPC and MFG-HSC were adjacent (less than 10m) to blood vessels. However, HSPC preferentially associated with transition zone vessels when compared to the MFG-HSC. In contrast the MFG-HSC were closer to the endosteum and sinusoids suggesting the existence of different microenvironments for HSC and downstream progenitors. Live imaging demonstrated that in the steady-state- the MFG-HSC were largely non-motile (moving less than 10m over a period of two hours) whereas the Mds1GFP+ HSPC migrated more and further. Treatment with chemotherapy and G-CSF -which dramatically induces HSC proliferation and mobilization into the circulation- led to the formation of clonal MFG-HSC clusters in endosteal regions undergoing both bone deposition and remodeling. This study demonstrates live imaging of a subset of minimally motile LT-HSC and suggests that a unique endosteal microenvironment supports MFG-HSC expansion after chemotherapy injury. Note that multiple studies have shown that less than 10% of LT-HSC localize near the endosteum and that most are associated with sinusoids in the central BM [12,17,21,23]. These suggest that the MFG-HSC represents a subset of HSC that specifically associates with the endosteum (). A subset of macrophages also localizes near the endosteal surface (osteomacs). These macrophages promote HSC retention in the bone marrow, and are suppressed after mobilizing doses of G-CSF [31,32]. It would be of great interest to the field to examine whether these osteomacs localize near the MFG-HSC as this will further support the existence of a discrete niche for amplifying and mobilizing HSC in response to stress.

Upadhaya et al., [27**] used Pdzk1ip1-CreER:tdTomato mice for live imaging of HSC. In these mice low dose tamoxifen expression results in TdTomato expression in 23% of LT-HSC. Live imaging of mouse calvarium or tibia showed that the labeled HSC are highly motile with ~90% of the labeled HSC moving more than 20m whereas ~10% of the labeled HSC showed minimal movement. Combining Pdzk1ip1-CreER:tdTomato with Fgd5ZsGreen or KitLGFP/+ reporter mice allowed visualization of endothelial cells or stem cell factor (SCF)-producing perivascular cells. These confirmed the perivascular location of HSC but also revealed that over short periods of time- HSC form multiple, close, transient contacts with various SCF-producing cells. Thus HSC might travel between different niches/microenvironments to receive different signals that regulate their behavior (). Surprisingly a drug treatment that inhibits the CXCR4 receptor and 41/91 integrins -and mobilizes HSC to the circulation- also blocked HSC movement in the BM. This indicates that HSC movement requires CXCL12-CXCR4 and/or integrin signaling.

Although additional analyses are needed to resolve the observed discrepancies in motility between the HSC examined, the Christodoulou et al., and Upadhaya et al., studies open the door to deciphering HSC regulation by different signals, in situ, with single cell resolution.

It is becoming increasingly clear that hematopoiesis in the bone marrow is spatially and regionally organized and that local cues produced by distinct microenvironments are responsible for regulating different HSPC. The best characterized example of this spatial heterogeneity is the data supporting the existence of distinct sinusoidal and arteriolar niches for HSC. As discussed in the previous sections most HSC localize reside exclusively in sinusoidal locations whereas smaller fractions also associate with arterioles and/or the endosteum [12,17,21,23,24,33*,34,35]. Note that the precise fractions of HSC associated which each structure and whether these associations are specific-remains a source of controversy. Each group has used different methods to identify HSC and different criteria to define proximity to each type of structure. These further highlight a need for a common criteria in the field for defining cell proximity to niche components. Also note that due to the abundance of sinusoids- almost all hematopoietic cells locate within 30m of a sinusoid [36]. Therefore an arteriolar niche or endosteal niche is going to also contain sinusoids [12,26**,36]. Kunisaki et al., showed that 30% of LinCD48CD150+ HSC localized near arterioles ensheathed by Ng2+ periarteriolar cells and that Ng2+ cell ablation caused loss of HSC quiescence and function [17]; another 30% of HSC specifically map within 5m of megakaryocytes and loss of megakaryocytes or megakaryocyte-derived CXCL4 or TGF resulted in HSC proliferation in sinusoidal locations without affecting HSC in arteriolar locations [21,22]. Pinho et al., found that von Willebrand factor (vWF) positive HSC, which are biased towards megakaryocyte fates [37] selectively localized near megakaryocytes (60% of vWF+ HSC are within 5m of a megakaryocyte) whereas vWF- HSC localized near arterioles. Megakaryocyte ablation specifically expanded vWF+ HSC [38]. Itkin et al., discovered that HSC could be fractionated based on intracellular ROS (reactive oxygen species) levels and that HSC with lower levels of ROS where enriched near arterioles whereas HSC with higher levels of ROS located near sinusoids [39]. Further data supporting a distinct arteriolar HSC niche was provided by Kusumbe et al., which showed that constitutive Notch signaling in the vasculature increased the number of arterioles in the BM followed by accumulation of HSC suggesting that arteriole number controls HSC abundance. Together these studies support the existence of a megakaryocyte/sinusoidal niche that maintains HSC biased towards megakaryocyte fates and an arteriolar niche that maintains more quiescent HSC ().

There is also evidence supporting the existence of a distinct endosteal HSC niche. After adoptive transfer into recipient mice the donor HSC are selectively enriched near endosteal cells [30,40,41]. In agreement Zhao et al., discovered that CD48CD49b HSC are resistant to chemotherapy and proposed that they represent a reserve HSC (rHSC) population. Sixteen percent of these rHSC localize -and amplify after chemotherapy near the endosteum, adjacent to N-cadherin+ stromal cells that support them [33*]. Live imaging analyses also demonstrated that after chemotherapy- a subset of HSC selectively proliferate in endosteal regions undergoing bone remodeling and deposition [26**]. Together these studies support the concept that the endosteum might provide a niche for regenerating HSC ().

The localization of progenitors downstream of HSC is less characterized. Multipotent progenitors are immediately below HSC in the hematopoietic hierarchy and are major contributors to blood cell production in the steady-state [13]. Live animal imaging of transplanted HSC -or a population enriched in MPP- into non-irradiated recipients showed that the MPP located further away from the endosteum [30]. In agreement live animal imaging of Mds1GFP+ HSPC also enriched in MPP- and MFG-HSC [26**] showed different spatial distributions for these two populations and increased HSPC localization near transitional vessels. These studies suggest that HSC and MPP might occupy different niches. In contrast, Cordeiro-Gomes et al., found similar spatial organization for HSC and MPP and in rare occasions- observed colocalization of HSC and MPP suggesting that they occupy the same niche [42]. Note that each of these studies used different markers/reporter mice to define HSC/HSPC/MPP as well as different imaging approaches (live imaging of transplanted cells/live imaging of subsets of HSC and HSPC in the calvarium/fixed femur whole mounts) and additional studies are needed to resolve the question on whether HSC and MPP (of which there are multiple subsets [43]) occupy the same or distinct niches.

Several components of the bone marrow microenvironment including endothelial cells [44,45], perivascular cells [4648], osteocytes [49], megakaryocytes [50], and even neutrophils [51] produce signals that support and regulate myeloid cell production in the steady-state and after stress (reviewed in [52]). However, the specific sites for myelopoiesis in the bone marrow, or whether myeloid progenitors and HSC share the same niche, remain unknown. This is mainly due to lack of approaches to image myeloid progenitors. Herault et al., were able to image a population of classically defined granulocyte monocyte progenitors (GMP) as Lin-Sca1-CD150-c-kit+FcR+ cells [50]. Note that subsequent studies have shown that these phenotypically defined GMP are heterogeneous and contain bipotent and unipotent monocyte and granulocyte progenitors [4,53]. Herault et al., showed that these heterogeneous GMP were almost always found as single cells, distributed through the bone marrow. Insults that trigger emergency myeloid cell production induced formation of tightly packed GMP clusters. This cluster formation required signals provided from the microenvironment [50] suggesting that specific regions of the bone marrow support emergency myeloid progenitor expansion in response to stress.

Similarly, lymphopoiesis is dependent on signals produced by perivascular stromal cells [42], endothelial cells [42], and osteoblastic lineage cells, which include osteoblastic progenitors, osteoblasts, and osteocytes [18,20,41,5459]. While these studies support the concept of an endosteal niche for lymphopoiesis the spatial localization of lymphoid progenitors is not clear. Ding et al., found that 30% of LinIL7Ra+ cells which are enriched in lymphoid progenitor- were in contact with the endosteum [18]. In contrast, Tokoyoda et al., found that B220+flk2+ pre-pro-B cells and B220+c-kit+ pro-B cells were scattered through the central bone marrow. Additionally, 65% of Pre-pro-B cells and 0% pro-B cells were in contact with CXCL12 producing reticular cells whereas 11% of Pre-pro-B cells and 89% of pro-B cells contacted IL7-producing reticular cells. These suggest a perivascular location for lymphopoiesis and that CXCL12 and IL7 producing stromal cells provide niches for different stages of lymphocyte maturation [60]. Surprisingly, Cordeiro-Gomes et al., found that IL7-producing cells are a subset of CXCL12-producing reticular cells and that Ly6D+ common lymphoid progenitors localize to this subset. Since HSC also associate with IL7+CXCL12+ reticular stromal cells [42] this also suggested that common lymphoid progenitors and HSC occupy the same niche. Additional studies are necessary to reconcile these findings.

Erythropoiesis is also regionally organized; classical studies demonstrated that a subset of macrophages that localize near sinusoids provides a niche that supports islands of erythroblasts maturation [61,62] (for a recent review see [63]). Recently, Comazzetto et al., were able to image Lin-Sca1-c-kit+CD105+ erythroid progenitors. These selectively localize to reticular stromal cells in perisinusoidal locations. These stromal cells maintained these adjacent progenitors via SCF secretion [64**]. These indicate that sinusoids are the site of erythropoiesis.

The bone marrow is highly organized and contains specialized regions that provide distinct microenvironments that selectively regulate unique types of hematopoietic cells (). The field has made tremendous progress in defining the spatial architecture of hematopoiesis. The development of approaches to image hematopoiesis in vivo will further transform the field by allowing visualization of cell decisions in real time. However, several challenges remain including: a) the lack of approaches to simultaneously image many types of hematopoietic progenitors and precursors. These prevent examination of stepwise differentiation in situ to determine how local signals impact progenitor function; b) scRNAseq analyses have identified several new types of stromal cells with unknown functions in hematopoiesis and shown that known populations e.g endothelial cells and perivascular cells- are highly heterogeneous with different subsets producing unique combinations of cytokines and growth factors [79**]. Visualization of these novel populations and subsets will likely lead to the identification of unique niches for hematopoietic progenitors and precursors. The development of novel techniques allowing imaging of cytokines in the BM [65*] will be invaluable for these approaches; c) the bone marrow extracellular matrix is increasingly being recognized as a key regulator of hematopoiesis [66] that is spatially organized [67]. How differentiating hematopoietic cells interact with the extracellular matrix remains poorly understood; d) most studies in the field have focused in dissecting how each type of cell in the microenvironment interacts with- and regulates- one type of HSPC. However, multiple stromal cell types cooperate to regulate each type of HSPC and different stromal cells regulate different stages of HSPC maturation [58,60,68]; how the bone marrow ensures that each HSPC localizes to the right microenvironment as they mature remains unknown. Answers to these questions will define how the spatial architecture of the bone marrow regulates hematopoiesis during homeostasis and disease and allow the development of culture systems containing all the niche structures to necessary to produce large amounts of blood ex vivo.

Key points:

The spatial organization of the bone marrow ensures that distinct microenvironments regulate different types of stem cells and progenitors.

The best studies microenvironments are HSC niches and mounting evidence supports the existence of distinct sinusoidal and arteriolar HSC niches.

It is becoming increasingly clear that the bone marrow contains distinct niches for progenitors downstream of HSC.

Despite tremendous progress the spatial organization of hematopoiesis remains poorly understood and new approaches are needed.

New live imaging studies of native HSC open the door to examine HSC regulation, in situ.

The author apologizes to colleagues whose work was not cited because of space constraints.

Financial support and sponsorship

This work was partially supported by the National Heart Lung and Blood Institute (R01HL136529 to D.L.).

Conflicts of interest

The author has no conflicts of interest

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