The blood stem cell research that could change medicine of the future

 

Making stem cells from a patient’s adult cells – rather than human embryos – is one of the holy grails in modern medicine treatments. New research brings us two steps closer.

Biomedical engineers and medical researchers at UNSW Sydney have independently made discoveries about embryonic blood stem cell creation that could one day eliminate the need for stem cell blood donors.

The achievements are part of a move in regenerative medicine towards the use of ‘induced pluripotent stem cells’ to treat disease, where stem cells are reverse engineered from adult tissue cells rather than using live human or animal embryos.

But while we have known about induced pluripotent stem cells since 2006, scientists still have plenty to learn about how cell differentiation in the human body can be mimicked artificially and safely in the lab for the purposes of delivering targeted medical treatment.

Two studies have emerged from UNSW researchers in this area that shine new light on not only how the precursor blood stem cells occur in animals and humans, but how they may be induced artificially.

In a study published today in Cell Reports, researchers from UNSW School of Biomedical Engineering demonstrated how a simulation of an embryo’s beating heart using a microfluidic device in the lab led to the development of human blood stem cell ‘precursors’, which are stem cells on the verge of becoming blood stem cells.

And in an article published in Nature Cell Biology recently, researchers from UNSW Medicine & Health revealed the identity of cells in mice embryos responsible for blood stem cell creation.

Both studies are significant steps towards an understanding of how, when, where and which cells are involved in the creation of blood stem cells. In the future, this knowledge could be used to help cancer patients, among others, who have undergone high doses of radio- and chemotherapy, to replenish their depleted blood stem cells.

Emulating the heart

In the study detailed in Cell Reports, lead author Dr Jingjing Li and fellow researchers described how a 3cm x 3cm microfluidic system pumped blood stem cells produced from an embryonic stem cell line to mimic an embryo’s beating heart and conditions of blood circulation.

She said that in the last few decades, biomedical engineers have been trying to make blood stem cells in laboratory dishes to solve the problem of donor blood stem cell shortages. But no one has yet been able to achieve it.

“Part of the problem is that we still don’t fully understand all the processes going on in the microenvironment during embryonic development that leads to the creation of blood stem cells at about day 32,” Dr Li said.

“So we made a device mimicking the heart beating and the blood circulation and an orbital shaking system which causes shear stress – or friction – of the blood cells as they move through the device or around in a dish.”

These systems promoted the development of precursor blood stem cells which can differentiate into various blood components – white blood cells, red blood cells, platelets and others. They were excited to see this same process – known as haematopoiesis – replicated in the device.

Study co-author Associate Professor Robert Nordon said he was amazed that not only did the device create blood stem cell precursors that went on to produce differentiated blood cells, but it also created the tissue cells of the embryonic heart environment that is crucial to this process.

“The thing that just wows me about this is that blood stem cells, when they form in the embryo, form in the wall of the main vessel called the aorta. And they basically pop out of this aorta and go into the circulation, and then go to the liver and form what’s called definitive haematopoiesis, or definitive blood formation.

“Getting an aorta to form and then the cells actually emerging from that aorta into the circulation, that is the crucial step required for generating these cells.”

“What we’ve shown is that we can generate a cell that can form all the different types of blood cells. We’ve also shown that it is very closely related to the cells lining the aorta – so we know its origin is correct – and that it proliferates,” A/Prof. Nordon said.

The researchers are cautiously optimistic about their achievement in emulating embryonic heart conditions with a mechanical device. They hope it could be a step towards solving challenges limiting regenerative medical treatments today: donor blood stem cell shortages, rejection of donor tissue cells, and the ethical issues surrounding the use of IVF embryos.

“Blood stem cells used in transplantation require donors with the same tissue-type as the patient,” A/Prof. Nordon said.

“Manufacture of blood stem cells from pluripotent stem cell lines would solve this problem without the need for tissue-matched donors providing a plentiful supply to treat blood cancers or genetic disease.”

Dr Li added: “We are working on up-scaling manufacture of these cells using bioreactors.”

Mystery solved

Meanwhile, and working independently of Dr Li and A/Prof. Nordon, UNSW Medicine & Health’s Professor John Pimanda and Dr Vashe Chandrakanthan were doing their own research into how blood stem cells are created in embryos.

In their study of mice, the researchers looked for the mechanism that is used naturally in mammals to make blood stem cells from the cells that line blood vessels, known as endothelial cells.

“It was already known that this process takes place in mammalian embryos where endothelial cells that line the aorta change into blood cells during haematopoiesis,” Prof. Pimanda said.

“But the identity of the cells that regulate this process had up until now been a mystery.”

Read more: Baby mice have a skill that humans want – and this microchip might help us learn it

In their paper, Prof. Pimanda and Dr Chandrakanthan described how they solved this puzzle by identifying  the cells in the embryo that can convert both embryonic and adult endothelial cells into blood cells. The cells – known as ‘Mesp1-derived PDGFRA+ stromal cells’ -– reside underneath the aorta, and only surround the aorta in a very narrow window during embryonic development.

Dr Chandrakanthan said that knowing the identity of these cells provides medical researchers with clues on how mammalian adult endothelial cells could be triggered to create blood stem cells – something they are normally unable to do.

“Our research showed that when endothelial cells from the embryo or the adult are mixed with ‘Mesp1 derived PDGFRA+ stromal cells’ – they start making blood stem cells,” he said.

While more research is needed before this can be translated into clinical practice – including confirming the results in human cells – the discovery could provide a potential new tool to generate engraftable haematopoietic cells.

“Using your own cells to generate blood stem cells could eliminate the need for donor blood transfusions or stem cell transplantation. Unlocking mechanisms used by nature brings us a step closer to achieving this goal,” Prof. Pimanda said.

For the entire article, please click on the link below:

https://newsroom.unsw.edu.au/news/health/blood-stem-cell-research-could-change-medicine-future

 

 

 

Streamlining stem cells to treat macular degeneration

Stem cell treatment and biology as a multicellular embryonic concept or adult organismas a symbol for cellular therapy as a 3D illustration.

As we age, so do our eyes; most commonly, this involves changes to our vision and new glasses, but there are more severe forms of age-related eye problems. One of these is age-related macular degeneration, which affects the macula — the back part of the eye that gives us sharp vision and the ability to distinguish details. The result is a blurriness in the central part of our visual field.

The macula is part of the eye’s retina, which is the light-sensitive tissue mostly composed of the eye’s visual cells: cone and rod photoreceptor cells. The retina also contains a layer called the retinal pigment epithelium (RPE), which has several important functions, including light absorption, cleaning up cellular waste, and keeping the other cells of the eye healthy.

The cells of the RPE also nourish and maintain the eye’s photoreceptor cells, which is why one of the most promising treatment strategies for age-related macular degeneration is to replace aging, degenerating RPE cells with new ones grown from human embryonic stem cells.

Scientist have proposed several methods for converting stem cells into RPE, but there is still a gap in our knowledge of how cells respond to these stimuli over time. For example, some protocols take a few months while others can take up to a year. And yet, scientists are not clear as to what exactly happens over that period of time.

Mixed cell populations

“None of the differentiation protocols proposed for clinical trials have been scrutinized over time at the single-cell level — we know they can make retinal pigment cells, but how cells evolve to that state remains a mystery,” says Dr Gioele La Manno, a researcher with EPFL’s Life Sciences Independent Research (ELISIR) program.

“Overall, the field has been so focused on the product of differentiation, that the path undertaken has been sometimes overlooked,” he adds. “For the field to move forward, it is important to understand aspects of the dynamics of what happens in these protocols. The path to maturity could be as important as the end state, for example for the safety of treatment or for improving cell purity and reducing production time.”

Tracking stem cells as they grow into RPE cells

La Manno has now led a study with Professor Fredrik Lanner at the Karolinska Institute (Sweden) profiling a protocol for differentiating human embryonic stem cells into RPE cells that is actually intended for clinical use. Their work shows that the protocol can develop safe and efficient pluripotent stem cell-based therapies for age-related macular degeneration. The study is published and featured on this month’s cover of the journal Stem Cell Reports.

“Standard methods such as quantitative PCR and bulk RNA-seq capture the average expression of RNAs from large populations of cells,” says Alex Lederer, a doctoral student at EPFL and one of the study’s lead authors. “In mixed-cell populations, these measurements may obscure critical differences between individual cells that are important for knowing if the process is unfolding correctly.” Instead, the researchers used a technique called single-cell RNA sequencing (scRNA-seq), which can detect all the active genes in an individual cell at a given time.

Looking at intermediate states

Using scRNA-seq, the researchers were able to study the entire gene expression profile of individual human embryonic stem cells throughout the differentiation protocol, which takes a total of sixty days. This allowed them to map out all the transient states within a population as they grew into retinal pigment cells, but also to optimize the protocol and suppress the growth of non-RPE cells, thus preventing the formation of contaminant cell populations. “The aim is to prevent mixed cell populations at the time of transplantation, and to make sure the cells at the endpoint are similar to original RPE cells from a patient’s eye,” says Lederer.

What they found was that on the way to becoming RPE cells, stem cells go through a process very similar to early embryonic development. During this, the cell culture took up a “rostral embryo patterning,” the process that develops the embryo’s neural tube, which will go on to become its brain and sensory systems for vision, hearing, and taste. After this patterning, the stem cells began to mature into RPE cells.

Eye-to-eye: transplanting RPE cells in an animal model

But the point of the differentiation protocol is to generate a pure population of RPE cells that can be implanted in patients’ retinas to slow down macular degeneration. So the team transplanted their population of cells that had been monitored with scRNA-seq into the subretinal space of two female New Zealand white albino rabbits, which are what scientists in the field refer to as a “large-eyed animal model.” The operation was carried out following approval by the Northern Stockholm Animal Experimental Ethics Committee.

The work showed that the protocol not only produces a pure RPE cell population but that those cells can continue maturing even after they have been transplanted in the subretinal space. “Our work shows that the differentiation protocol can develop safe and efficient pluripotent stem cell-based therapies for age-related macular degeneration,” says Dr Fredrik Lanner, who is currently making sure the protocol can be soon used in clinics.

For the entire article link, please click below:

https://www.sciencedaily.com/releases/2022/06/220614122635.htm

 

What Is a Platelet-Rich Plasma (PRP) Facial?

 

As we age, we notice many changes in our bodies. Many obvious changes take place in our skin. Do you have wrinkles and facial lines that you want to get rid of without surgery? Well, the vampire facial or plasma-rich protein (PRP) facial may be your answer. It triggers collagen production and, via micro-needling, it improves skin tone and texture.

Platelet-rich plasma (PRP) facials became popular with plastic surgery because of their role in wound healing. PRP has a high concentration of platelets. which allows for the formation and release of growth factors and active proteins that promote healing. It is widely used in facial skin rejuvenation.

What is the PRP Procedure for the Face?

PRP facials are not cosmetic procedures, but rather medical procedures. The person doing the procedure takes a sample of your blood and isolates the protein-rich plasma and platelets to create the PRP.

A centrifuge is spun around to extract protein-rich plasma. The platelets are also removed. The sample is then concentrated and called platelet-rich plasma (PRP). The high levels of growth factors in the PRP help the body to heal. Dermatologists began using PRP to promote the growth of collagen. Orthopedics inject PRP to heal joints of the knees, ankles, and elbows.

The full effect of PRP facial treatments appears in a few weeks to months. PRP is given to enhance someone’s appearance, so the cost is not covered by medical insurance.

How Does the PRP Facial Work?

There are different ways to get the PRP facial. In the first option, the plasma is spread on your face, after which micro-needling across the forehead and cheeks helps the face absorb proteins. Microneedling is a procedure that makes a series of superficial, tiny holes using sterile needles. Both the micro-needling and the PRP stimulate collagen growth.

PRP Benefits for Face

The PRP facial can be beneficial to people who have wrinkles, sun damage, or scars. By placing PRP back into the skin, cell proliferation is encouraged. This leads to an increase in elastin and collagen production. As a result, the skin will look tighter, fuller, and smoother.

In the areas with deeper wrinkles and lines, the doctor may also choose to use hyaluronic acid fillers or neuromodulators. These are Botox®-like wrinkle relaxing injections. Fillers restore the volume to the face that is naturally lost with aging. Facial muscles are kept from contracting by the neuromodulators. The neuromodulators help to reduce lines that occur from muscle overuse. This is inclusive of crow’s feet surrounding the eyes. These products can be used together to treat the whole face.

For more information, please contact Miami Stem Cell (305) 598-7777 to schedule a free consultation with one of our US-Board Certified physicians. www.stemcellmia.com

Evaluation of Platelet-Rich Plasma Therapy for Peripheral Nerve Regeneration: A Critical Review of Literature

From the Department of Hand Surgery, China-Japan Union Hospital of Jilin University, Changchun, China

Peripheral nerve injury (PNI) is a common disease in clinic, and the regeneration process of peripheral nerve tissue is slow, and patients with PNI often suffer from the loss of nerve function. At present, related research on the mechanism of peripheral nerve regeneration has become a hot spot, and scholars are also seeking a method that can accelerate the regeneration of peripheral nerve. Platelet-rich plasma (PRP) is a platelet concentrate extracted from autologous blood by centrifugation, which is a kind of bioactive substance. High concentration of platelets can release a variety of growth factors after activation, and can promote the proliferation and differentiation of tissue cells, which can accelerate the process of tissue regeneration. The application of PRP comes from the body, there is no immune rejection reaction, it can promote tissue regeneration with less cost, it is,therefore, widely used in various clinical fields. At present, there are relatively few studies on the application of PRP to peripheral nerve regeneration. This article summarizes the literature in recent years to illustrate the effect of PRP on peripheral nerve regeneration from mechanism to clinical application, and prospects for the application of PRP to peripheral nerve.

Introduction

Peripheral nerve injury is a common nervous system condition associated with a high disability rate. Currently, the best treatment for nerve injury is restoring nerve continuity through microsurgical tension-free anastomosis or autogenous nerve transplantation. This treatment approach does not improve slow nerve regeneration and incomplete postoperative functional recovery. Thus, regeneration and repair of peripheral nerve injury is the focus of intense research.

Although injured nerve can be reconstructed the continuity, this, however, does not create a suitable microenvironment of nerve regeneration (Fowler et al., 2015). Platelet rich plasma (PRP) is a concentration of autologous platelets that releases various growth factors, hence promoting tissue regeneration. PRP has many applications. For example, in stomatology, a randomized controlled clinical trial showed that PRP and its derivatives prevent alveolar bone atrophy and enhance alveolar tissue regeneration (Ucak Turer et al., 2020). A multicenter, double-blind, randomized controlled trial in foot and ankle surgery showed that PRP injection outperforms traditional glucocorticoid injection in plantar aponeurosis treatment (Peerbooms et al., 2019). In sports medicine, a double-blind randomized control study showed that PRP injection can effectively improve healing of old meniscus injury (Kaminski et al., 2019). In chronic sports injury treatment, it is reported that pain relief and functional recovery of lateral humeral epicondylitis (tennis elbow) patients receiving PRP are better relative to controls (Mishra et al., 2014Merolla et al., 2017). In joint surgery, local PRP injection effectively relieves pain in patients with knee joint osteoarthritis, promoting functional recovery and its effects are superior to traditional hyaluronic acid (Duymus et al., 2017Lisi et al., 2018). In ophthalmology, PRP can be used to treat secretory dry eye (García-Conca et al., 2019). PRP is also reported to significantly accelerate wound healing (Mohamadi et al., 2019Zhang et al., 2019). PRP applications are summarized in Table 1.

Table 1

www.frontiersin.orgTABLE 1. Summary of clinical application of PRP.

In conclusion, decades of clinical practice show that PRP promotes tissue repair and regeneration. Moreover, this approach does not need special equipment and training, and is cost effective, making it of great value in regenerative medicine (Etulain, 2018). Here, we comprehensively review the effects of PRP on peripheral nerve regeneration, the mechanisms underlying PRP promotion of peripheral nerve regeneration, and PRP clinical applications for peripheral nerve regeneration.

For the entire article, please click on the link below, or to learn more about this PRP treatment, visit: www.stemcellmia.com

https://www.frontiersin.org/articles/10.3389/fbioe.2022.808248/full

 

Stem Cells for Urinary Incontinence: Functional Differentiation or Cytokine Effects?

 

 

Minimally-invasive stem cell therapy for stress urinary incontinence may provide an effective nonsurgical treatment for this common condition. Clinical trials of periurethral stem cell injection have been underway and basic science research has demonstrated the efficacy of both local and systemic stem cell therapies. Results differ as to whether stem cells have a therapeutic effect by differentiating into permanent, functional tissues, or whether they exert benefits through a transient presence and the secretion of regenerative factors. This review explores the fate of therapeutic stem cells for stress urinary incontinence and how this may relate to their mechanism of action.

Introduction

Urinary incontinence afflicts up to 1 in 2 women. It poses significant economic and quality of life burdens, with over $32 billion annual U.S. dollars spent managing it. Stress urinary incontinence (SUI) impacts up to 1 in 4 women and accounts for over $12 billion annual U.S. dollars in health care costs. Incontinence imparts major psychosocial burdens on those afflicted by it, and places women at risk for other debilitating conditions, including depression, anxiety, low self-esteem, social isolation, infection, pain, and sexual dysfunction. Therefore, a clear need to develop cost-effective, durable, and minimally invasive treatment for the condition exists.

Some patients with SUI effectively respond to conservative treatment, including pelvic floor physical therapy, biofeedback, pelvic floor electrical stimulation, or continence devices, such as pessaries. Several surgical and transurethral treatments are also available, including peri-urethral bulking injections and sub-urethral slings, which are the gold standard therapy for the condition. Slings offer the highest long-term cure rate for SUI, but like any surgery, are not without complications, which include sling erosion, urinary retention, bladder perforation, wound issues, and pain. Moreover, reports of complications involving vaginal mesh, while not pertaining to mid-urethral slings, have negatively swayed public opinion about such procedures. To date, besides conservative treatments, injectable therapies used to coapt the urethral lumen remain the least invasive SUI treatments providing some clinical benefit. These interventions produce no visible scars, but have largely fallen from clinical favor due to limited durability and efficacy.

The utilization of stem cells and other progenitor cells as injectable agents, via a similar approach as bulking agents, present potential alternate therapies. Stem cells are unique due to their ability to proliferate, self-renew, and produce a population of differentiated progeny, making them a promising therapy in the field of regenerative medicine. To date, stem cells have been classified into four main categories. Embryonic stem cells (ESCs) derived from human blastocysts represent the most undifferentiated form, possessing the ability to differentiate into any human cell type. Theoretically, they provide the greatest therapeutic potential but their use is restricted by ethical concerns, as well as potential allogenicity and tumor oncogenesis. Amniotic fluid-derived stem cells (AFSCs) are a second form. This heterogeneous cell population is isolated from the amniotic fluid or placental membrane of a developing fetus, but their proliferation potential is only intermediate along the stem cell spectrum. Like ESCs, AFSCs can differentiate into many different cell lineages, but they are felt to possess lower tumorigenicity. A third form are differentiated, somatic cells that are “reprogrammed” into pluripotent cells. These induced pluripotent stem cells (IPSCs) possess similar differentiation potential to ESCs but preclude the necessity of an embryo. The utility of IPSCs in regenerative urology requires further investigation. Lastly, adult stem cells (ASCs) represent the most well understood type. These are tissue-specific progenitor cells, which are the most limited on the spectrum of differentiation. Mesenchymal stem cells (MSCs) are a subset of ASCs that can be isolated from bone marrow and induced to differentiate into various cell lineages. Recently, alternative sources of ASCs, such as muscle-derived stem cells (MDSCs) and adipose-derived stem cells (ADSCs) have been obtained with less invasive techniques compared to MSCs.

In the pre-clinical setting, a variety of SUI models exist for investigating pathophysiology and treatment. Leak point pressure (LPP), a measure of urethral resistance to leakage, determined by measuring bladder pressure at the time of leak, is a frequently utilized surrogate for SUI. Methods to decrease urethral resistance in order to elicit SUI are numerous and include direct urethral injury, urethrolysis, pudendal nerve injury, and vaginal distension. Bladder pressure can be increased to induce leakage using direct bladder compression, sneeze testing, or direct infusion using a suprapubic catheter. Additional assessments of these models include measurement of urethral closure pressure, testing of EUS function via electromyography (EMG), and histological studies of the EUS investigating muscle content and organization.

This review addresses various applications of stem cells and progenitor cells to SUI, with a focus on recent developments in the field. The article also gives specific consideration to the mechanisms of therapeutic benefit from such cells, as well as implications for future studies and clinical applications. Commentary on the economic aspects of regenerative therapy for SUI is also included.

For the entire article / clinical trial, please click on the link below:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345159/

 

DOCTORS FEEL HOPEFUL ABOUT RESTORING TASTE AND SMELL LOSS AFTER COVID

The second phase of a clinical trial for patients to regain their sense of taste and smell is about to begin, and it is showing promising results.

Otolaryngologist Dr. David Rosen has been helping patients restore their sense of taste and smell after respiratory infections for two decades. When the COVID-19 pandemic hit, a concerning number of people were experiencing this overwhelming side effect. Traditional therapy to treat this condition can require a painful injection directly up the nostril to the olfactory nerve. But, Dr. Rosen began trying a less invasive treatment using a topical application of platelet-rich plasma (PRP) into the nose to stimulate cell regrowth and restore taste and smell. This therapeutic approach, which shows some success, is now entering into phase II clinical trial. Nancy, a patient suffering from persistent anosmia after a COVID diagnosis in 2021, shared how this trial has helped her senses begin to return.

We spoke with Dr. Rosen and otolaryngologists, Drs. Glen D’Souza and Alexander Duffy, about how the clinical trial is helping patients.

How is COVID causing loss of taste and smell?

Rosen: COVID is directly binding to the lining of the nose through a particular receptor called the ACE-2 receptor. The nose lining gets damaged, along with the cells it supports called the olfactory cells, commonly known as the smell cells. Because they lose the supporting cells, the olfactory cells can’t function properly.

How does treatment to regain taste and smell begin?

Rosen: First, we prescribe an oral steroid, work with patients through olfactory training (smell training), and suggest they begin taking supplements, such as V vitamin A, alpha-lipoic acid, sodium citrate, or omega 3. They can also use an over-the-counter nasal steroid. If they don’t recover within six months, we start trying more aggressive treatments, such as the one used in our clinical trial.

Can you tell us more about the treatment offered in the clinical trial?

Rosen: We are taking a patient’s blood and spinning it down to remove the red cells and saving the plasma, which has all the platelets in it. We take the PRP, and we apply that topically into the nose. This helps the cells regenerate because PRP can help cell regeneration throughout the body, for example, hair regrowth.

For the entire article, please click on the link below or for more information, contact Miami Stem Cell (305) 598-7777

Doctors Feel Hopeful About Restoring Taste and Smell Loss After COVID