Stem Cell Biology Archives - Sanford Burnham Prebys

Category: Stem Cell Biology

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Using stem cells to study the biochemistry of learning

AuthorMiles Martin
Date

August 18, 2022

Neural networks grown from human stem cells

A method for studying human neurons could help researchers develop approaches for treating Alzheimer’s, schizophrenia and other neurological diseases

Researchers from the Conrad Prebys Center for Chemical Genomics have developed a procedure to use neurons derived from human stem cells to study the biological processes that control learning and memory. The method, described in Stem Cell Reports, uses electrodes to measure the activity of neuronal networks grown from human-induced pluripotent stem cells (iPSCs). The procedure tracks how synapses—the connections between neurons—strengthen over time, a process called long-term potentiation (LTP).

“Impaired long-term potentiation is thought to be central to many neurological diseases, including Alzheimer’s, addiction and schizophrenia,” says senior author Anne Bang, PhD, director of Cell Biology at the Prebys Center. “We’ve developed an approach to study this process in human cells much more efficiently than current methods, which could help trigger future breakthroughs for researchers working on these diseases.”

LTP helps our brain encode information, which is what makes it so critical for learning and memory. Impairment of LTP is thought to contribute to neurological diseases, but it has proven difficult to verify this hypothesis in human cells.

LTP helps our brain encode information, which is what makes it so critical for learning and memory. Impairment of LTP is thought to contribute to neurological diseases, but it has proven difficult to verify this hypothesis in human cells.

Anne Bang, PhD, director of Cell Biology at the Prebys Center.

“LTP is such a fundamental process,” says Bang. “But the human brain is hard to study directly because it’s so inaccessible. Using neurons derived from human stem cells helps us work around that.”

Although LTP can be studied in animals, these studies can’t easily account for some of the more human nuances of neurological diseases.

“A powerful aspect of human stem cell technology is that it allows us to study neurons produced from patient stem cells. Using human cells with human genetics is important in these types of tests because many neurological diseases have complex genetics underpinning them, and it’s rarely just one or two genes that influence a disease,” adds Bang.

To develop the method, first author and Prebys Center staff scientist Deborah Pré, PhD, grew networks of neurons from healthy human stem cells, added chemicals known to initiate LTP and then used electrodes to monitor changes in neuronal activity that occurred throughout the process.

The method can run 48 tests at once, and neurons continue to exhibit LTP up to 72 hours after the start of the experiment. These are distinct advantages over other approaches, which can often only observe parts of the process and are low throughput, which can make getting results more time consuming.

For this study, the researchers used neurons grown from healthy stem cells to establish a baseline understanding of LTP. The next step is to use the approach on neurons derived from patient-derived stem cells and compare these results to the baseline to see how neurological diseases influence the LTP process.

“This is an efficient method for interrogating human stem cell–derived neurons,” says Bang. “Doing these tests with patient cells could open doors for researchers to discover new ways of treating neurological diseases.”

Institute News

Hospitals were full. One scientist stepped up.

AuthorMonica May
Date

February 10, 2021

Evan Snyder, MD PhD headshot

Sanford Burnham Prebys physician-scientist Evan Snyder spent two weeks in a gymnasium-turned-ICU, where he cared for people with severe COVID-19

The novel coronavirus has hit California hard, but one area that has been particularly impacted is Imperial County. Last spring, the rural farming region’s two hospitals became overwhelmed with COVID-19 cases—prompting a college basketball stadium to be converted into a makeshift intensive care unit (ICU). Soon, qualified personal were also needed.

Stem cell scientist Evan Snyder, MD, Ph.D., may not be the first person you would think to call on during such an emergency. But as a physician-scientist who works with critically ill newborns, he knows his way around an ICU. He knows how to run ventilators. And perhaps most importantly, he had an urgent desire to help.

“I had already decided I would study this disease from a scientific perspective,” says Snyder, who is working with UC San Diego’s Sandra Leibel, MD, to use “mini lungs” to understand why some people with COVID-19 fare worse than others. “But as I started to see the public health menace it became, I felt like I needed to do more.”

Snyder started to sign up for every volunteer opportunity he could find. However, it wasn’t until the December post-holiday surge in cases when he was deployed to serve in the field. Through the California Medical Assistance Team (CAL-MAT), a group of highly trained medical professionals who provide assistance during disasters, Snyder was deployed to the gym-turned-ICU in Imperial County.

“Although our research examines the impact of the virus on lung cells created from people of many racial and ethnic backgrounds, the degree of disease disparity didn’t hit me at a gut level until this work,” says Snyder. “There’s no question that COVID-19 is unfairly hitting people who are socio-economically challenged and have co-morbidities such as diabetes and hypertension, which are the often the products of a disadvantaged environment.”
 

“I was like a vampire”

For two weeks Snyder worked through the night, taking down medical histories; giving people oxygen, providing medications such as dexamethasone, remdesivir, anticoagulants and antibiotics; carefully turning people onto their stomachs to ease breathing difficulties or helping individuals walk. He also saw clear patterns emerge.

All of the people he treated had conditions that are linked to poverty. More than 20% of people living in Imperial County live below the poverty line—double the national average. As a result, residents may be more likely to obtain food from food banks and may not have access to regular healthcare—which together can lead to conditions such as diabetes, hypertension or obesity. Many of the people whom Snyder cared for shared that they lived in small quarters with multiple generations, which made quarantining difficult, if not impossible.

“Some people who live in La Jolla and test positive have the luxury of living in a big house. They can afford not to go to work and stay in a separate bedroom while the rest of the family quarantines,” says Snyder. “The people I took care of can’t do that. We need to create places where people who test positive for COVID-19 can quarantine safely away from their families.”

Carrying insights back to the lab

Snyder’s experience has directly informed several new research avenues he plans to pursue.

“We already model real-world COVID-19 infections with ‘mini lungs’ created from different genders and races,” explains Snyder. “But this taught me that we need to better mimic the conditions present in a person who has diabetes or other conditions that create an adverse milieu for their organs and cells.”

This work also imprinted upon him that COVID-19 is more than a lung condition. The risk of blood clots causing strokes, heart attacks or blocking blood flow to the lungs was an ever-present concern.

“It wasn’t just about giving people more oxygen,” says Snyder. “This showed me that we need to focus even more on the vascular and inflammatory components of this disease.”
 

Lives were saved

Snyder is relieved to report that no lives were lost during those two weeks. He credits the care given—even if relatively primitive—to this success.

“If we weren’t doing what we were doing, about 30% of the people there would have died. And another 30% would have been left with lifelong impairments,” says Snyder. “However, in order to truly tame this virus, we need to find effective drugs, continue to vaccinate as many people as possible and exercise logical public health precautions.”

Institute News

Scientists “turn back time” on cancer using new stem cell reprogramming technique

AuthorMonica May
Date

August 21, 2020

human cells

Discovery opens new research avenues that may help catch cancer early and identify potential preventive treatments

Scientists at Sanford Burnham Prebys Medical Discovery Institute have reprogrammed cancer cells back into their pre-cancer identity—opening new doors for studying how cancer develops and how it might be prevented. The research, published in Stem Cell Reports, may lead to tests that identify cancer early on, when it can be more easily treated, and uncover preventive treatments that stop cancer before it starts.

“We believe we have been able to contribute to one of the major goals of modern cancer research: creating next-generation models for studying how cancer develops from its earliest state,” says Evan Snyder, MD PhD, professor and director of the Center for Stem Cells & Regenerative Medicine at Sanford Burnham Prebys and senior author of the study. “We essentially took an adult cancer that has accumulated many mutations and pushed it back to the earliest stages of development, allowing us to emulate a tumor’s premalignant state. Then we watched cancer emerge from normal cells before our eyes.”

Turning back the clock on cancer 

In the study, the scientists set out to transform cells from anaplastic thyroid tumors—an aggressive, fast-growing cancer that is nearly always diagnosed at late stages—into induced pluripotent stem cells (iPSCs). These cells model the embryonic cells that are present at the earliest stages of human development and can become any cell in the body. While iPSCs are used today to create unlimited supplies of cells for research and therapeutic purposes—usually to correct abnormalities—the scientists recognized that tumor-derived iPSCs could be used to study the development of cancer.

However, this feat turned out to be easier said than done. The standard reprogramming method didn’t work, requiring the researchers to hunt for a different method that would induce the cancer cells to reset. Inhibiting a protein called RAS was the key ingredient that coaxed these thyroid cancer cells to become normal iPSC cells.

“We have named the pathway that is critical for making a cancer cell act as if it were a normal cell its ‘reprogram enablement factor,’” explains Snyder. “That factor will likely be different for every cancer and, in fact, may help in defining that cancer type.

“For this cancer type, which we examined in our study as a proof-of-concept, the reprogram enablement factor turned out to be blunting an overactive RAS pathway,” Snyder continues. “Our results suggest that losing control of RAS was the ‘big bang’ for this cancer—the very first event that leads to out-of-control cell growth and development of a tumor.”

The scientists next plan to reprogram additional cancers—including brain and lung cancer—into iPSCs to determine their “reprogram enablement factors.” If successful, they will next map the molecular changes that occur immediately before and after the tumors develop, which could reveal early signals of cancer and new preventive or early treatment measures.

“Unlike other cells, cancer cells are notoriously resistant to reprogramming,” says Snyder. “Our study is the first to successfully reprogram cancer cells into completely normal iPSCs, which opens new doors for cancer research.”

A team effort

The first author of the study is Yanjun Kong of Sanford Burnham Prebys and Shanghai Jiao Tong University. Yang Liu of Sanford Burnham Prebys is a co-corresponding author. Additional study authors include Ryan C. Gimple of UC San Diego; Rachael N. McVicar, Andrew P. Hodges and Jun Yin of Sanford Burnham Prebys; and Weiwei Zhan of Shanghai Jiao Tong University.

This study was funded by the Stem Cell Research Center & Core Facility at Sanford Burnham Prebys and by the China Scholarship Council (201606230202). The study’s DOI is 10.1016/j.stemcr.2020.07.016.

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SBP’s Alexey Terskikh advances hair growth research

AuthorMonica May
Date

August 16, 2018

Illustration of a hair follicle

Three years ago, Alexey Terskikh, PhD, associate professor in Sanford Burnham Prebys Medical Discovery Institute’s (SBP’s) Development, Aging and Regeneration Program, published a groundbreaking study showing that stem cells could be used to grow hair.

This discovery could help more than 80 million men, women and children in the United States experiencing hair loss. Across cultures, personal identity is connected with hair. As a result, hair loss often affects emotional well-being and self-esteem. There is clear interest in the technology: Our 2015 story on this finding remains our blog’s most-read article. 

Since then, Terskikh and his team have been working hard to advance this technology. We caught up with Terskikh to learn about his progress—and how far away the research remains from human studies. 

Alexey Terskikh ​
     Alexey Terskikh, PhD

Could you fill us in on your work since 2015?

For the past three years, my team and I have been working to overcome several obstacles to the technology’s real-world use. We’ve made progress on multiple fronts, summarized below:

Generating unlimited cells 
Instead of embryonic stem cells, which are difficult to obtain, our method now uses induced pluripotent stem cells (iPSC), which are derived from a simple blood draw or skin sample. iPSCs allow us to create an unlimited supply of cells to grow hair. Not having enough hair is one reason current transplants don’t work, so this is a critical advance.

Creating a natural look
Hair actually grows in a specific direction, so it’s important to control the orientation of hair growth to achieve a natural look. Your hair stylist is familiar with this!

We’ve found a solution—3D biodegradable scaffolds—and partnered with leading scientists in the field to advance our project. The scaffold allows us to control the number of cells transplanted, their direction and where they are placed.

Helping the transplant “take”
The scaffold has a second job of helping seed hair follicles. Skin is a good barrier—that’s its job—so we needed something to help the transplant “take.” The scaffold provides the “soil” from which the hair can grow. 

Hair-generating cells in mouse skin​
Hair-inducing human cells (red)
generated from iPSC present within hair
follicles grown in mouse skin. 

I understand you have formed a company based on this research. Can you tell us more? 

Yes, we have formed a company this year and assembled a great team with the expertise needed to move the technology forward. These experts include hair transplantation specialists, experienced entrepreneurs and experts in manufacturing cells at large scale (not a trivial endeavor). 

While hair loss affects people’s self-esteem and self-image, it isn’t life threatening, so it’s not a top priority for many funding agencies. Forming a company gives us a vehicle for raising capital to advance this technology.

Do you know how the stem cell–generated hair will look? Can you control hair color? 
We hope that stem cell–generated hair will look exactly as the original hairs that have been lost. Of course, it will take some time to grow a “perfect” hair, but we believe this should be possible in the long run.

Has anything surprised you during this process? 
I expected to hear from young and older men, but I was surprised by the number of women who reached out to express interest in our research. I received about an equal number of emails from women. Pregnancy, menopause and ovarian conditions may all cause hair loss for women. 

Most heartbreaking were emails from parents of children with alopecia, a condition where a child cannot grow hair. As you can imagine, hair loss at such a young age can affect relationship formation and self-image. All these emails continue to motivate me to keep advancing this research as quickly as possible.

What work needs to be done before you can test this on humans? How far away are we from this product being used on humans?

The good news is that we’ve resolved the biological mystery of hair growth using stem cells. Now, it is mostly an engineering exercise: how to get robust and properly oriented hair growth. 

Before we can discuss human studies with the U.S. Food and Drug Administration (FDA), we need to complete safety and tumorigenicity tests in mice. We are performing these tests very soon. 

Provided we have the proper funding, we expect it will take two years before we can start discussions with the FDA.

Assuming all goes as planned and the FDA approves a first-in-human study, will everyone be eligible for the trial? 

At that point we will work very closely with clinical experts in the field to determine which individuals are most likely to benefit from this research and should be involved in the trial. 

How did you first get started on this research? 

That’s actually a funny story. My father—who is a scientist—wanted to stay more in touch, so we decided to do a joint project. I was researching stem cells, and he was researching skin follicles, so we ended up here! If you look at the paper, you’ll see two authors who have the same last name—him and me. 

Interested in keeping up with SBP’s latest discoveries, upcoming events and more? Subscribe to our monthly newsletter, Discoveries.

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Teaching stem cells to build muscle

Authorjmoore
Date

February 18, 2016

Header image

Researchers in Alessandra Sacco’s lab have found a key to enhancing repair of damaged muscle. In work published in Cell Reports, they describe why fetal muscle stem cells (MuSCs) are better at regenerating muscle compared to adult MuSCs. The research opens the door for new approaches to treat muscle diseases including muscular dystrophies, which affect approximately 50,000 people in the U.S., and muscle wasting associated with cancer and aging.

“We found that fetal MuSCs remodel their microenvironment by secreting specific proteins, and then examined whether that same microenvironment can encourage adult MuSCs to more efficiently generate new muscle. It does, which means that how adult MuSCs normally support muscle growth is not an intrinsic characteristic, but can be changed,” explained Matthew Tierney, a graduate student at SBP and first author of the study.

The proteins that fetal MuSCs secrete are part of the extracellular matrix (ECM), the meshwork of strand-like proteins and starches that make up the structure of MuSCs’ microenvironment. As fetal MuSCs mature into adult MuSCs, they take on different responsibilities and help change their microenvironment over time to support their distinct functions. Fetal MuSCs are geared toward creating new muscle, whereas adult MuSCs repair damaged muscle and self-replicate to sustain the pool of stem cells to mend future injuries.

In muscular dystrophies and muscle wasting, progressive degeneration overwhelms the regenerative capacity of adult MuSCs. The new study showing that adult MuSCs living in a microenvironment with fetal characteristics are better at regenerating muscle provides rationale for developing drugs that could trigger this transition.

“These results help explain the differences between the capacity of fetal and adult MuSCs to repair muscle. Such an understanding is urgently needed, as no treatments are yet available for muscular dystrophies and muscle-wasting disorders,” stated Alessandra Sacco, PhD, associate professor in the Development, Aging, and Regeneration Program at SBP and senior author of the study.

“Our findings fit with the growing appreciation of the importance of a cell’s structural and biochemical surroundings in influencing cellular behavior. Managing the microenvironment is an emerging approach to treat many diseases, from cancer to cardiovascular disease to neurodegeneration. We’re excited about the implications of our research for treating muscle diseases, and look forward to applying our conclusions toward development of therapies.”

The full text of the paper is available here.

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Researchers resolve longstanding issue of components needed to regenerate muscle

Authorsgammon
Date

February 9, 2016

Header image

Researchers at SBP have conclusively identified the protein complex that controls the genes needed to repair skeletal muscle. The discovery clears up deep-rooted conflicting data and will now help streamline efforts towards boosting stem cell-mediated muscle regeneration. Such strategies could treat muscle degenerative diseases such as muscular dystrophies, and those associated with aging and cancer. Continue reading “Researchers resolve longstanding issue of components needed to regenerate muscle”

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SBP supports opening of stem cell exhibit at the Reuben H. Fleet Science Center

Authorjmoore
Date

January 29, 2016

Header image

Pamela Itkin-Ansari, PhD, adjunct assistant professor in the Development, Aging, and Regeneration Program at SBP, participated in the grand opening event for the Super Cells exhibit at the Fleet on Jan. 28. She served as an expert on the current understanding of stem cells, answering questions and explaining what stem cell researchers do. Continue reading “SBP supports opening of stem cell exhibit at the Reuben H. Fleet Science Center”

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New Department of Defense grant funds efforts to treat ALS with stem cells

Authorjmoore
Date

January 28, 2016

Header image

Evan Snyder, MD, PhD, director of the Center for Stem Cells and Regenerative Medicine and a professor in SBP’s Human Genetics Program, was awarded a grant to develop a stem cell treatment for amyotrophic lateral sclerosis (ALS). ALS, also known as Lou Gehrig’s disease, involves degeneration and death of motor neurons (which control voluntary muscles), causing difficulty speaking, swallowing, and eventually breathing. No available treatments can slow the progression of ALS, which affects approximately 20,000 people in the U.S.

As new therapies are urgently needed, the Department of Defense announced a funding program for new therapeutic ideas in ALS in 2015. Snyder received one of eight grants awarded in this competitive program.

This grant will support research on human neural stem cells (hNSCs) as an approach to support the survival and function of existing motor neurons. The Snyder lab is modifying hNSCs so that they can be administered via the bloodstream and home to the spinal cord. This strategy allows the stem cells to become distributed throughout the spinal cord, overcoming a previous limitation. Snyder’s team has already shown that transplanted NSCs improved motor performance, respiratory function, and symptom-free survival in a mouse model of ALS.

hNSCs are already in phase I clinical trials for ALS, which have shown that this therapy is safe. These trials were possible in part because of the Snyder lab’s pioneering work in preclinical models. The current research promises to lead to an improved version of this therapy.

Institute News

New study sheds light on cancer stem cell regulation

Authorsgammon
Date

February 5, 2015

Header image

Researchers at Sanford-Burnham have discovered a precise stem cell signaling process that can lead to intestinal tumors if disrupted. The findings add to our understanding of how stem cells give rise to tumors and identify specific stem cell molecules that may be targeted to prevent the onset, progression, and recurrence of intestinal cancers. The results of the study appear online in Cell Reports today. Continue reading “New study sheds light on cancer stem cell regulation”

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Stem cells grow new hair – Arabic translation

Authorsgammon
Date

January 27, 2015

hair growth

“دراسة جديدة لنمو الشعر”

في دراسة جديدة، إستخدم الباحثون في معهد سان- برونهام الخلايا الجذعه المحفزة1 في جسم الإنسان لتعمل على توليد ونمو الشعر الجديد. وتمثل هذه الدراسة خطوة أولى نحو تطوير علاج عن طريق الخلايا الجذعية للأشخاص الذين يعانون من مشكلة فغداً الشعر “الصلع” .في الولايات المتحدة وحدها، يعاني أكثر من 40 مليون رجل و 21 مليون إمرأة من مشكلة فقدان الشعر، ولقد تم نشر هذا البحث على الإنترنت في بلوس وان. 

تبرعكم سوف يصنع الفرق الرجاء التبرع للدكتور ألكسي للمضي قدما في هذا الإنجاز.

“لقد قمنا بتطوير طريقة إستخدام الخلايا الجذعية المحفزه لخلق خلية جديدة قادرة على بدء نمو الشعر عند الإنسان”. و قال ألكسي ترسكي و هو دكتور أستاذ مشارك في معهد التنميه، والشيخوخة و برامج التجديد ” طريقة إستعمال الخلايا الجذعية توفر مصدرا غير محدود من الخلايا من المريض لعملية زراعة الشعر وهي ليست محدودة كالطرق المستعملة حالياً عن طريق إستخدام ونزع بصيلات الشعر المتواجدة من الأصل. طور فريق البحث نظام يعمل على تمايز الخلايا الجذعية المحفزة عند الإنسان لتصبح وتتحول إلى خلايا جلدية حليمة. هذه الخلايا الجلدية تعد خلايا فريده من نوعها وتعمل على تنظيم تشكيل بصيلات الشعر و دورة نموه. هذه الخلايا الجلدية لا تعد مناسبة لنمو الشعر من تلقاء نفسها لأنها لا تتوفر بالكميات المطلوبة وتفقد قدرتها بسرعة على حث تشكيل بصيلات الشعر بدون عمله التمايز مع الخلايا الجذعية. 

عند البالغين، هذه الخلايا الجلدية يمكن تضخيمها خارج الجسم، وأنها سرعان ما تفقد خصائصها في عملية تحفيز الشعر”.يقول الدكتور ألكسي “لقد قمنا بإبتكار نظام يعمل لدفع الخليا الجذعية المحفزه عند الإنسان لتتمايز أو تتحول إلى خلايا جلدية حليمة، وقد أكد نجاح التجربة حيث أكد على قدرة هذه الخلايا على حث نمو الشعر عند زرعها عند الفئران”. خطوتنا التاليه هي زراعة الخلايا الجذعية المحفزة عند الإنسان مرة أخرى إلى جسم الإنسان، و نحن حالياً نسعى إلى شركات لتنفيذ الخطوة الأخيرة”. 

شاهد المزيد على الرابط 
 

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