Stem Cell Clinic

Breakthrough in Stem Cell Research: First Image of Niche Environment | Newsroom – UC Merced University News

By Lorena Anderson, UC Merced

Professor Joel Spencer and his lab have made a huge breakthrough in stem cell research.

Professor Joel Spencer was a rising star in college soccer and now he is an emerging scientist in the world of biomedical engineering, capturing for the first time an image of a hematopoietic stem cell (HSC) within the bone marrow of a living organism.

Everyone knew black holes existed, but it took until last year to directly capture an image of one due to the complexity of their environment, Spencer said. Its analogous with stem cells in the bone marrow. Until now, our understanding of HSCs has been limited by the inability to directly visualize them in their native environment until now.

This work brings an advancement that will open doors to understanding how these cells work which may lead to better therapeutics for hematologic disorders including cancer.

Understanding how HSCs interact within their local environments might help researchers understand how cancers use this same environment in the bone marrow to evade treatment.

Spencer studied biological sciences at UC Irvine where he was the captain of the mens Division 1 soccer team. He initially planned to pursue a career in professional soccer until faculty mentors opened doors for research and introduced Spencer to biophotonics the science that deals with the interactions of light with biological matter.

UC faculty were a big part of my research experience; they became mentors and friends, Spencer said. My first foray into research was as a lab tech, and that is where I met people who were doing biomedical imaging, and it just caught my wonder.

An image of a stem cell in its natural niche

Spencer left his native California to earn his Ph.D. in bioengineering at Tufts University in Boston and took a postdoctoral research position in the Wellman Center for Photomedicine at Massachusetts General Hospital and Harvard Medical School. In Boston, he learned about live-animal imaging and his wonder became a passion.

Now his emphasis is on biomedical optics: building new microscopes and new imaging techniques to visualize and study biological molecules, cells and tissue in their natural niches in living, fully intact small animals.

I work at the interface of engineering and biology. My lab is seeking to answer biological questions that were impossible until the advancements in technology we have seen in the past couple decades, he said. You need to be able to peer inside an organ inside a live animal and see whats happening as it happens.

Based on work conducted at UC Merced and in Boston, he and his collaborators including his grad student Negar Tehrani visualized stem cells inside the bone marrow of live, intact mice.

He and his collaborators have a new paper published in the journal Nature detailing the work they conducted to study HSCs in their native environment in the bone marrow.

We can see how the cells behave in their native niches and how they respond to injuries or stresses which seems to be connected to the constant process of bone remodeling, Tehrani said. Researchers have been trying to answer questions that have gone unanswered for lack of technology, and they have turned to engineering to solve those puzzles.

Its important for researchers to understand the mechanics of stem cells because of the cells potential to regenerate and repair damaged tissue.

Spencer, left, and students from his lab

Spencer returned to California three years ago, joining the Department of Bioengineering in the School of Engineering at UC Merced. Hes also an affiliate of the Health Sciences Research Institute and the NSF CREST Center for Cellular and Biomolecular Machines . This is his third paper in Nature, but the first stemming from work conducted in his current lab.

He didnt come to UC Merced just because he loves biology Spencer also joined the campus because of the students.

Now Im back in the UC system Im a homegrown UC student whos now faculty, Spencer said. As a student within the system I was able to participate in myriad opportunities, including mentorships that advanced my career. Now I try to encourage graduate and undergrad students to follow their dreams. I love being able to give them opportunities its something I really want to do for the next generation.

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Breakthrough in Stem Cell Research: First Image of Niche Environment | Newsroom - UC Merced University News

University of Delaware researcher receives $250K grant for new biotherapies – Technical.ly Brooklyn

As part of a pilot search for new medical breakthroughs, the partnership of King of Prussia-based plasma-based biotech company CSL Behring and the University City Science Center in Philadelphia has awarded $250,000, plus the opportunity to work alongside CSL Behring experts, to Eleftherios (Terry) Papoutsakis, Ph.D., of the University of Delaware, for his exploration of cell derived micro-particles and vesicles (MkMPs) for the treatment of thrombocytopenias and in stem-cell targeted gene therapies.

Papoutsakis is one of two researchers to receive the award, called the CSL Behring-Science Center Research Acceleration Initiative. The other, Cecelia Yates, Ph.D. of the University of Pittsburgh, uses biomimetic peptides as potential targeted therapeutic treatment of pulmonary fibrosis.

This initiative is another example of the strength of our partnership with the Philadelphia-based University City Science Center as we look in our backyard for innovative scientific advancements that have the potential to help rare disease patients lead full lives, said Dr. Bill Mezzanotte, EVP and head of research and development for CSL Behring, in a press release. Our growing R&D organization looks forward to working with Dr. Yates and Dr. Papoutsakis in the years ahead to advance their scientific research.

The therapy that Dr. Papoutsakis is developing involves gene editing of stem cells that may potentially benefit to patients for a variety of genetic blood disorders such as Wiskott-Aldrich syndrome.

The CSL Behring Science Center Research Initiative is currently accepting applications from researchers in the region developing therapeutic biotechnologies in immunology, neurology, haematology, thrombosis, transplant, respiratory and cardiovascular/metabolic to receive one of up to three grants in 2020 of up to $400,000 each. The deadline is April 13.

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University of Delaware researcher receives $250K grant for new biotherapies - Technical.ly Brooklyn

Scientists Think They Know How Stress Causes Gray Hair – Thrive Global

Sorry Mom and Dad: It turns out you might not have been exaggerating when you told us your children made your hair turn gray.

Stress may play a key role in just how quickly hair goes from colored to ashen, astudyTrusted Sourcepublished this past week in the journal Nature suggests.

Scientists have long understood some link is possible between stress and gray hair, but this new research from Harvard University in Massachusetts more deeply probes the exact mechanisms at play.

The researchers initial tests looked closely at cortisol, the stress hormone that surges in the body when a person experiences a fight or flight response.

Its an important bodily function, but the long-term presence of heightened cortisol is linked to a host ofnegative health outcomes.

But the culprit ended up being a different part of the bodys fight or flight response the sympathetic nervous system.

These nerves are all over the body, including making inroads to each hair follicle, the researchers reported.

Chemicals released during the stress response specifically norepinephrine causes pigment producing stem cells to activate prematurely, depleting the hairs reserves of color.

The detrimental impact of stress that we discovered was beyond what I imagined,Ya-Chieh Hsu, PhD, a lead study author and an associate professor of stem cell and regenerative biology at Harvard, said in apress release. After just a few days, all of the pigment-regenerating stem cells were lost. Once theyre gone, you cant regenerate pigments anymore. The damage is permanent.

But stress isnt the only or even the primary reason that most people get gray hair.

In most cases, its simple genetics.

Gray hair is caused by loss of melanocytes (pigment cells) in the hair follicle. This happens as we age and, unfortunately, there is no treatment that can restore these cells and the pigment they produce, melanin,Dr. Lindsey A. Bordone, a dermatologist at ColumbiaDoctors and an assistant professor of dermatology at Columbia University Medical Center in New York, told Healthline. Genetic factors determine when you go gray. There is nothing that can be done medically to prevent this from happening when it is genetically predetermined to happen.

That doesnt mean environmental factors such as stress dont play a role.

Smoking, for instance, is a known risk factor for premature graying, according to a2013 studyTrusted Source. So kick the habit if you want to keep that color a little longer.

Other contributing factors to premature graying include deficiencies in protein, vitamin B-12, copper, and iron as well as aging due in part to an accumulation of oxidative stress.

That stress is prompted by an imbalance between free radicals and antioxidants in your body that can damage tissue, proteins, and DNA,Kasey Nichols, NMD, an Arizona physician and a health expert atRave Reviews, told Healthline.

And some degree of oxidative stress is a natural part of life.

We would expect increasing gray hair as we advance in age, and we see about a 10 percent increase in the chance of developing gray hair for every decade after age 30, Nichols said.

Changes you can pursueto delay premature grays include eating a diet high in omega-3 fatty acids such as walnuts and fatty fish, not spending too much time in the skin-damaging and hair-damaging ultraviolet light of the sun, and taking vitamin B-12 and vitamin B-6 supplements.

That said, if you are going gray prematurely, it wouldnt hurt to go have a checkup just in case natural genetic factors arent the sole culprit.

The new Harvard research is only a mouse study, so replicating the same results in a human study would be necessary to strengthen the findings.

But the Harvard research has implications far beyond graying hair, with the hair color change merely one obvious sign of other internal changes as a result of prolonged stress.

By understanding precisely how stress affects stem cells that regenerate pigment, weve laid the groundwork for understanding how stress affects other tissues and organs in the body, said Hsu. Understanding how our tissues change under stress is the first critical step towards eventual treatment that can halt or revert the detrimental impact of stress.

Might that also mean someday halting and reverting the march of premature gray hair? Its too soon to tell.

We still have a lot to learn in this area, Hsu said.

Originally published on Healthline.

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Scientists Think They Know How Stress Causes Gray Hair - Thrive Global

Isolated Extramedullary Relapse in Acute Lymphoblastic Leukemia: What Can We Do Before and After Transplant? – Cancer Network

Santiago Riviello-Goya, MD1; Aldo A. Acosta-Medina, MD2; Sergio I. Inclan-Alarcon, MD3; Sofa Garcia-Miranda, MD2; and Christianne Bourlon, MD, MHSc2

1Department of Medicine, Instituto Nacional de Ciencias Mdicas y Nutricin Salvador Zubirn, Mexico City, Mexico; 2Department of Hematology, Instituto Nacional de Ciencias Mdicas y Nutricin Salvador Zubirn, Mexico City, Mexico; 3Cancer Center, Centro Mdico ABC, Mexico City, Mexico

A 43-year-old male with a history of B-cell acute lymphoblastic leukemia (ALL), who underwent allogeneic hematopoietic stem cell transplantation (HSCT) 5 months prior, presented to the emergency department with a 5-day history of progressive bilateral lower extremity weakness. On physical examination, there were no additional neurologic findings; sensory function and urethral and anal sphincter tone were preserved.

Initial clinical laboratory testing showed peripheral blood cell counts, a peripheral blood smear, and a comprehensive metabolic panel within normal limits. Neuroimaging by computed tomography (CT) and magnetic resonance showed no evidence of acute intracranial processes or lesions suggestive of leukemic relapse. A lumbar puncture for cerebrospinal fluid (CSF) analysis was performed and documented the presence of lymphoid-appearing blasts (Figure 1). Flow cytometry (FC) confirmed central nervous system (CNS) infiltration by B-lineage lymphoid blasts (CD34+, CD45+, CD22+, CD19+, and CD10+) (Figure 2). Bone marrow aspirate and biopsy, including FC evaluation, were negative for systemic relapse. Bone marrow chimerism was 98%.

With a diagnosis of isolated extramedullary leukemic relapse (iEMR), the patient was initiated on weekly intrathecal chemotherapy and was weaned off graft-versus-host disease (GVHD) prophylaxis, achieving CSF clearance after 4 weeks of therapy. Against Hematology service recommendations, the patient declined systemic therapy and received only whole brain radiation therapy (24 Gy in 12 fractions).

The patient experienced remission of neurologic symptoms; however, after 5 months, he developed bilateral testicular tenderness and enlargement. An ultrasound was performed and was suggestive of leukemic infiltration (Figure 3). Chemotherapy with methotrexate and L-asparaginase in addition to radiotherapy to the testes (24 Gy in 12 fractions) was given without complications.

One year after initial CNS iEMR, the patient developed overt bone marrow relapse (BMR), as evidenced by development of bone pain throughout the lumbosacral region, and the appearance of multiple blastic and lytic lesions throughout the appendicular and axial skeleton. A positron emission tomography-CT scan documented abdominal lymphadenopathy (Figure 4). With this rapidly progressive picture, the patient was transitioned to supportive care and died 2 months later.

Is the risk of iEMR following HSCT modified by the choice of conditioning regimen? If so, which of the following approaches would have been the best choice to prevent iEMR in this patient?

A. There is no role of conditioning therapy in preventing iEMRB. Reduced intensity of regimen to favor graft-versus-leukemia (GVL) effectC. Nonmieloablative regimens including fludarabineD. Mieloablative regimens including total body irradiation (TBI)

CORRECT ANSWER: D. Mieloablative regimens including total body irradiation (TBI).

Allogeneic HSCT is an effective treatment for ALL, which can achieve long-term remission and even a potential cure.1 Antineoplastic activity is dependent on both high-dose chemotherapy and graft alloreactivity, with the latter manifested in the GVL effect, and undesirably yet inherently, in GVHD.2 Despite recent advances in allogeneic HSCT strategies, disease relapse is common and remains the most important cause of death in this population. Relapse is reported in 30% to 40% of patients but can increase to 60% in patients who are in a second complete remission (CR) at time of HSCT.2,3

Risk factors for relapse in patients with ALL who have undergone HSCT include disease- and transplant-related features. Reported high-risk disease characteristics include: hyperleukocytosis at diagnosis (white blood cell count >30 x109/L for B-lineage ALL and >100 x109/L for T-lineage ALL); cytogenetics associated with poor outcomes, including chromosome 11 translocations and t(9;22); a short remission timespan; more than a first CR; and a failed or delayed remission after induction therapy.4 In the HSCT population, transplant-related factors should be considered, including alternative donors other than those who are matched related and matched unrelated, the type of conditioning regimen, and the development of GVHD.2

ALL relapse following HSCT most commonly involves the medullary compartment, with a cumulative incidence of 41% at 5 years. Conversely, extramedullary relapse (EMR) is uncommon, with a 5-year cumulative incidence of 11.0% and 5.8% for EMR and iEMR, respectively.5 Due to the rarity of EMR, its prognostic impact remains controversial and the ideal management strategies are a subject of active study.

EMR is associated with poor clinical outcomes; however, the subgroup of patients with iEMR (as presented in this patient case) is gaining attention due to its increasing frequency, its role heralding a systemic relapse, and its clinical behavior showing better survival outcomes compared with BMR and EMR.6-8

Isolated EMR is defined as the presence of clonal blasts in any tissue other than the medullary compartment; bone marrow evaluation must show less than 5% of clonal blasts and a full donor chimerism. Most commonly affected sites include the skin, soft tissues, lymph nodes, and immune sanctuaries including the CNS and testes.1,5,9 Because prevention rather than treatment of relapse is related to improved survival outcomes, it is important to define subgroups of patients who may benefit fromearly intervention with a personalized transplant strategy.

Higher rates of iEMR have been linked to patients of younger age. This is thought to be secondary to: (1) a higher incidence of ALL compared with acute myeloid leukemia (AML) in this age subgroup, the former of which is most associated with EMR; (2) the relative overrepresentation of myelomonocytic/monocytic phenotypes in AML presenting in young individuals; and (3) the higher likelihood of a history of EMR in children compared with adults.1,10

A history of extramedullary (EM) disease, which has consistently been found to impact the development of iEMR, is preexistent in up to half of patients. In 2 out of 3 cases of EMR, disease affects the site of original EM involvement, possibly due to low efficacy of both high-dose chemotherapy and the GVL effect.1,5 An exception to this is CNS involvement, despite being a risk factor for subsequent CNS iEMR, which is commonly reported de novo, reflecting the protective effect of regularly administered prophylaxis to patients at high risk of CNS infiltration.11

The effect of GVHD on risk of iEMR is highly nuanced. Despite its well-known role as a protective factor for BMR, the same effect does not appear to hold true for iEMR.12 Initial reports in this population showed no differences in relapse-free survival regardless of acute or chronic GVHD (cGVHD) or a positive association between extensive cGVHD and iEMR development.10,13 This has led to investigators to postulate that the underlying physiopathology differs among different types of relapse, with decreased expression of human leukocyte antigen (HLA) minor histocompatibility antigens and adhesion molecules and decreased penetration of both immune cells and high-dose chemotherapy to EM sites.14 These mechanisms lead to decreased effectivness of T-cell dependent cytotoxicity of donor lymphocytes as compared with the medullary compartment, with subsequent clone selection and escape, enabling the development of iEMR.6

With the increased use of alternative donors, this has been contested in the haploidentical setting, with a recent report showing significantly increased rates of iEMR in patients who do not develop cGVHD. It is suggested that the role of GVL, coupled with GVHD, in this HLA-mismatched setting could partially explain the added benefit of GVHD in this subgroup. This report also evidenced increased tumor chemosensitivity in patients with EMR compared with BMR, possibly explained by reduced concentrations of conditioning therapy at EM sites.9

Cytogenetics associated with poor outcomes and advanced disease at the time of HSCT were described as risk factors for iEMR in initial cohort studies.1,5,10,15,16 However, recent publications that include alternative-donor HSCT recipients have reported that a haploidentical source could overcome this negative impact.9

The influence of type of conditioning regimen on likelihood of iEMR has been studied only retrospectively, mainly comparing TBI-based versus chemotherapy-based approaches. The landmark paper by Simpson et al showed a significantly elevated rate of iEMR in patients receiving busulfan-based conditioning. This finding has been related to the lack of penetration of drugs into the immune sanctuaries with chemotherapy-only regimens.17

Multiple approaches, including combination and single treatment for iEMR, have been described. Combination therapy including systemic chemotherapy plus local radiotherapy (or in CNS disease, radiation to the craniospinal axis, intrathecal chemotherapy, and systemic chemotherapy) has been associated with higher response rates than single-treatment strategies.9 Nonetheless, the best responses have been observed when combination therapy is followed by a cellular therapy (eg, second allogeneic HSCT, donor leukocyte infusion, and donor stem cell infusion), leading to CR rates of greater than 80%.5,13 Whether this increase in CR rate translates to an increase in survival outcomes remains debatable due to conflicting results in the current literature for iEMR.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Corresponding author:

Christianne Bourlon, MD, MHScVasco de Quiroga No. 15.Belisario Domnguez Seccin XVI

Tlalpan, C.P. 14080, Ciudad de Mxico, Mxico

E-mail: chrisbourlon@hotmail.com

References:

1. Ge L, Ye F, Mao X, et al. Extramedullary relapse of acute leukemia after allogeneic hematopoietic stem cell transplantation: different characteristics between acute myelogenous leukemia and acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2014;20(7):1040-1047. doi: 10.1016/j.bbmt.2014.03.030.

2. Pavletic SZ, Kumar S, Mohty M, et al. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. Biol Blood Marrow Transplant. 2010;16(7):871-890. doi: 10.1016/j.bbmt.2010.04.004.

3. Devillier R, Crocchiolo R, Etienne A, et al. Outcome of relapse after allogeneic stem cell transplant in patients with acute myeloid leukemia. Leuk Lymphoma. 2013;54(6):1228-1234. doi: 10.3109/10428194.2012.741230.

4. Hoelzer D, Bassan R, Dombret H, Fielding A, Ribera JM, Buske C; ESMO Guidelines Committee. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 5):v69-v82. doi: 10.1093/annonc/mdw025.

5. Shem-Tov N, Saraceni F, Danylesko I, et al. Isolated extramedullary relapse of acute leukemia after allogeneic stem cell transplantation: different kinetics and better prognosis than systemic relapse. Biol Blood Marrow Transplant. 2017;23(7):1087-1094. doi: 10.1016/j.bbmt.2017.03.023.

6. Lee JH, Choi SJ, Lee JH, et al. Anti-leukemic effect of graft-versus-host disease on bone marrow and extramedullary relapses in acute leukemia. Haematologica. 2005;90(10):1380-1388.

7. Xie N, Zhou J, Zhang Y, Yu F, Song Y. Extramedullary relapse of leukemia after allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore). 2019;98(19):e15584. doi: 10.1097/MD.0000000000015584.

8. Shi JM, Meng XJ, Luo Y, et al. Clinical characteristics and outcome of isolated extramedullary relapse in acute leukemia after allogeneic stem cell transplantation: a single-center analysis. Leuk Res. 2013;37(4):372-377. doi: 10.1016/j.leukres.2012.12.002.

9. Mo XD, Kong J, Zhao T, et al. Extramedullary relapse of acute leukemia after haploidentical hematopoietic stem cell transplantation: incidence, risk factors, treatment, and clinical outcomes. Biol Blood Marrow Transplant. 2014;20(12):2023-2028. doi:10.1016/j.bbmt.2014.08.023.

10. Harris AC, Kitko CL, Couriel DR, et al. Extramedullary relapse of acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcomes. Haematologica. 2013;98(2):179-184. doi: 10.3324/haematol.2012.073189.

11. Hamdi A, Mawad R, Bassett R, et al. Central nervous system relapse in adults with acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20(11):1767-1771. doi: 10.1016/j.bbmt.2014.07.005.

12. Giralt SA, Champlin RE. Leukemia relapse after allogeneic bone marrow transplantation: a review. Blood. 1994;84(11):3603-3612.

13. Solh M, DeFor TE, Weisdorf DJ, Kaufman DS. Extramedullary relapse of acute myelogenous leukemia after allogeneic hematopoietic stem cell transplantation: better prognosis than systemic relapse. Biol Blood Marrow Transplant. 2012;18(1):106-112. doi: 10.1016/j.bbmt.2011.05.023.

14. Kolb HJ. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood. 2008;112(12):4371-4383. doi: 10.1182/blood-2008-03-077974.

15. Lee KH, Lee JH, Choi SJ, et al. Bone marrow vs extramedullary relapse of acute leukemia after allogeneic hematopoietic cell transplantation: risk factors and clinical course. Bone Marrow Transplant. 2003;32(8):835-842. doi: 10.1038/sj.bmt.1704223.

16. Clark WB, Strickland SA, Barrett AJ, Savani BN. Extramedullary relapses after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome. Haematologica. 2010;95(6):860-863.

17. Simpson DR, Nevill T, Shepherd JD, et al. High incidence of extramedullary relapse of AML after busulfan/cyclophosphamide conditioning and allogeneic stem cell transplantation. Bone Marrow Transplant. 1998;22(3):259-264. doi: 10.1038/sj.bmt.1701319.

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Isolated Extramedullary Relapse in Acute Lymphoblastic Leukemia: What Can We Do Before and After Transplant? - Cancer Network