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News Article | May 1, 2017
Site: www.eurekalert.org

IMAGE:  Ovarian cancer tumors with higher percentages of cIAP-expressing cells, shown in red at left, were more sensitive to a potential combination therapy than tumor cells without cIAP-expressing cells. view more Researchers have been trying to understand why up to 85 percent of women experience recurrence of high-grade serous ovarian cancer -- the most common subtype of ovarian cancer -- after standard treatment with the chemotherapy drug carboplatin. Preclinical research from Dr. Sanaz Memarzadeh, who is a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, has potentially solved this mystery and pinpointed a combination therapy that may be effective for up to 50 percent of women with ovarian cancer. Memarzadeh's research, published in the journal Precision Oncology, shows a new combination therapy of carboplatin and an experimental drug called birinapant can improve survival in mice with ovarian cancer tumors. Additional findings reveal that testing for a specific protein could identify ovarian tumors for which the treatment could be effective. Importantly, the treatment could also target cancers that affect other parts of the body, including the bladder, cervix, colon and lung cancer. In 2015, Memarzadeh and her team uncovered and isolated carboplatin-resistant ovarian cancer stem cells. These cells have high levels of proteins called cIAPs, which prevent cell death after chemotherapy. Since the cancer stem cells survive carboplatin treatment, they regenerate the tumor; with each recurrence of ovarian cancer, treatment options become more limited. Memarzadeh showed that birinapant, which degrades cIAPs, can make carboplatin more effective against some ovarian cancer tumors. "I've been treating women with ovarian cancer for about two decades and have seen firsthand that ovarian cancer treatment options are not always as effective as they should be," said Memarzadeh, director of the G.O. Discovery Lab and member of the UCLA Jonsson Comprehensive Cancer Center. "Our previous research was promising, but we still had questions about what percentage of tumors could be targeted with the birinapant and carboplatin combination therapy, and whether this combination could improve overall survival by eradicating chemotherapy-resistant ovarian cancer tumors." In this new study, the research team first tested whether the combination therapy could improve survival in mice. Half of the mice tested had carboplatin-resistant human ovarian cancer tumors and the other half had carboplatin-sensitive tumors. The team administered birinapant or carboplatin as well as the two drugs combined and then monitored the mice over time. While birinapant or carboplatin alone had minimal effect, the combination therapy doubled overall survival in half of the mice regardless of whether they had carboplatin-resistant or carboplatin-sensitive tumors. "Our results suggest that the treatment is applicable in some, but not all, tumors," said Rachel Fujikawa, a fourth year undergraduate student in Memarzadeh's lab and co-first author of the study. To assess the combination therapy's rate of effectiveness in tumors, the team went on to test 23 high-grade serous ovarian cancer tumors from independent patients. Some were from patients who had never been treated with carboplatin and some were from patients who had carboplatin-resistant cancer. With these samples, the researchers generated ovarian cancer tumors utilizing a method called disease-in-a-dish modeling and tested the same treatments previously tested in mice. Once again, carboplatin or birinapant alone had some effect, while the combination of birinapant and carboplatin successfully eliminated the ovarian cancer tumors in approximately 50 percent of samples. Importantly, the combination therapy worked for both carboplatin-resistant and carboplatin-sensitive tumors. The researchers also measured cIAPs (the target for the drug birinapant) in the tumors. They found a strong correlation between cancer stem cells with high levels of cIAP and a positive response to the combination therapy. Since elevated levels of cIAPs have been linked to chemotherapy resistance in other cancers, the researchers wondered if the combination therapy could effectively target those cancers as well. The team created disease-in-a-dish models using human bladder, cervix, colon and lung cancer cells and tested the combination therapy. Similar to the ovarian cancer findings, 50 percent of the tumors were effectively targeted and high cIAP levels correlated with a positive response to the combination therapy. "I believe that our research potentially points to a new treatment option. In the near future, I hope to initiate a phase 1/2 clinical trial for women with ovarian cancer tumors predicted to benefit from this combination therapy," said Memarzadeh, gynecologic oncology surgeon and professor at the David Geffen School of Medicine at UCLA. The research was supported by an American Cancer Society Research Scholar Grant (RSG-14-217-407 01-TBG), the Phase One Foundation, the Ovarian Cancer Circle Inspired by Robin Babbini, a STOP Cancer Margot Lansing Memorial Seed award, the National Institutes of Health (R01CA183877 and #U54 MD007598) and the UCLA Broad Stem Cell Research Center.


News Article | April 20, 2017
Site: www.eurekalert.org

New research by scientists at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA overturns a long-standing paradigm about how axons -- thread-like projections that connect cells in the nervous system -- grow during embryonic development. The findings of the study, led by Samantha Butler, associate professor of neurobiology, could help scientists replicate or control the way axons grow, which may be applicable for diseases that affect the nervous system, such as diabetes, as well as injuries that sever nerves. As an embryo grows, neurons -- the cells in the nervous system -- extend axons into the developing spinal cord. Axons are then guided to reach other areas of the body, such as the brain, to establish a functioning nervous system. It has been generally understood that various guidance cues, which are cellular molecules such as proteins, either attract or repel axon growth as the axons reach out from neurons to find their destination in the nervous system. Previous research suggested that a particular guidance cue, called netrin1, functions over a long distance to attract and organize axon growth, similar to how a lighthouse sends out a signal to orient a ship from afar. However, previous research also shows that netrin1 is produced in many places in the embryonic spinal cord, raising questions about whether it really acts over a long distance. Most notably, netrin1 is produced by tissue-specific stem cells, called neural progenitors, which can create any cell type in the nervous system. Yet, it was not understood how the netrin1 produced by neural progenitors influences axon growth. Butler and her research team removed netrin1 from neural progenitors in different areas in mouse embryonic spinal cords. This manipulation resulted in highly disorganized and abnormal axon growth, giving the researchers a very detailed view of how netrin1 produced by neural progenitors influences axons in the developing nervous system. They found that neural progenitors organize axon growth by producing a pathway of netrin1 that directs axons only in their local environment and not over long distances. This pathway of netrin1 acts as a sticky surface that encourages axon growth in the directions that form a normal, functioning nervous system. Butler's study is a significant reinterpretation of the role of netrin1 in nervous system formation. The results further scientists' understanding of the contribution neural progenitors make to neural circuit formation. Determining how netrin1 specifically influences axon growth could help scientists use netrin1 to regenerate axons more effectively in patients whose nerves have been damaged. For example, because nerves grow in channels, there is much interest in trying to restore nerve channels after an injury that results in severed nerves, which is seen often in patients who have experienced an accident or in veterans with injuries to their arms or legs. One promising approach is to implant artificial nerve channels into a person with a nerve injury to give regenerating axons a conduit to grow through. Butler believes that coating such nerve channels with netrin1 could further encourage axon regrowth. Her continued research will focus on uncovering more details about how netrin1 functions and how it could be used clinically. Butler is the senior author of the study. The first author is Supraja Varadarajan, a graduate student in Butler's lab. The study is published today in the journal Neuron. The study was funded by grants from the National Institutes of Health (DK097075, HL098294, HL114457, DK082509 HL109233, DK109574, HL119837, NS072804, NS089817, NS063999, NS085097 and HL133900), the Canadian Institutes of Health Research (MOP-97758 and MOP- 77556), Brain Canada, the Natural Sciences and Engineering Research Council of Canada, Canada Foundation for Innovation, the W. Garfield Weston Foundation, the March of Dimes Foundation (6-FY10-296 and 1-FY07-458) and the UCLA Broad Stem Cell Research Center.


Corselli M.,University of California at Los Angeles | Corselli M.,Broad Stem Cell Research Center | Chin C.J.,University of California at Los Angeles | Parekh C.,Childrens Hospital Los Angeles | And 14 more authors.
Blood | Year: 2013

Hematopoietic stem and progenitor cells (HSPCs) emerge and develop adjacent to blood vessel walls in the yolk sac, aorta-gonad-mesonephros region, embryonic liver, and fetal bone marrow. In adult mouse bone marrow, perivascular cells shape a "niche" for HSPCs. Mesenchymal stem/stromal cells (MSCs), which support hematopoiesis in culture, are themselves derived in part from perivascular cells. In order to define their direct role in hematopoiesis, we tested the ability of purified human CD146+ perivascular cells, as compared with unfractionated MSCs and CD146- cells, to sustain human HSPCs in coculture. CD146+ perivascular cells support the long-term persistence, through cell-to-cell contact and at least partly via Notch activation, of human myelolymphoid HSPCs able to engraft primary and secondary immunodeficient mice. Conversely, unfractionated MSCs and CD146- cells induce differentiation and compromise ex vivo maintenance of HSPCs. Moreover, CD146+ perivascular cells express, natively and in culture, molecular markers of the vascular hematopoietic niche. Unexpectedly, this dramatic, previously undocumented ability to support hematopoietic stem cells is present in CD146+ perivascular cells extracted from the nonhematopoietic adipose tissue. © 2013 by The American Society of Hematology.


Zangle T.A.,University of California at Los Angeles | Teitell M.A.,University of California at Los Angeles | Teitell M.A.,Broad Stem Cell Research Center | Reed J.,Virginia Commonwealth University
Analyst | Year: 2012

Live cell mass profiling is a promising new approach for rapidly quantifying responses to therapeutic agents through picogram-scale changes in cell mass over time. A significant barrier in mass profiling is the inability of existing methods to handle pleomorphic cellular clusters and clumps, which are more commonly present in patient-derived samples or tissue cultures than are isolated single cells. Here we demonstrate automated Live Cell Interferometry (LCI) as a rapid and accurate quantifier of the sensitivity of single cell and colony-forming human breast cancer cell lines to the HER2-directed monoclonal antibody, trastuzumab (Herceptin). The relative sensitivities of small samples (<500 cells) of four breast cancer cell lines were determined tens-to-hundreds of times faster than is possible with traditional proliferation assays. These LCI advances in clustered sample assessment and speed open up the possibility for therapeutic response testing of patient-derived solid tumor samples, which are viable only for short periods ex vivo and likely to be in the form of cell aggregates and clusters. © 2012 The Royal Society of Chemistry.


Huang K.,Broad Stem Cell Research Center | Wu Z.,Tongji University | Liu Z.,Tongji University | Hu G.,Tongji University | And 10 more authors.
Human molecular genetics | Year: 2014

Immunodeficiency, centromeric instability and facial anomalies type I (ICF1) syndrome is a rare genetic disease caused by mutations in DNA methyltransferase (DNMT) 3B, a de novo DNA methyltransferase. However, the molecular basis of how DNMT3B deficiency leads to ICF1 pathogenesis is unclear. Induced pluripotent stem cell (iPSC) technology facilitates the study of early human developmental diseases via facile in vitro paradigms. Here, we generate iPSCs from ICF Type 1 syndrome patient fibroblasts followed by directed differentiation of ICF1-iPSCs to mesenchymal stem cells (MSCs). By performing genome-scale bisulfite sequencing, we find that DNMT3B-deficient iPSCs exhibit global loss of non-CG methylation and select CG hypomethylation at gene promoters and enhancers. Further unbiased scanning of ICF1-iPSC methylomes also identifies large megabase regions of CG hypomethylation typically localized in centromeric and subtelomeric regions. RNA sequencing of ICF1 and control iPSCs reveals abnormal gene expression in ICF1-iPSCs relevant to ICF syndrome phenotypes, some directly associated with promoter or enhancer hypomethylation. Upon differentiation of ICF1 iPSCs to MSCs, we find virtually all CG hypomethylated regions remained hypomethylated when compared with either wild-type iPSC-derived MSCs or primary bone-marrow MSCs. Collectively, our results show specific methylome and transcriptome defects in both ICF1-iPSCs and differentiated somatic cell lineages, providing a valuable stem cell system for further in vitro study of the molecular pathogenesis of ICF1 syndrome. GEO accession number: GSE46030. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.


News Article | December 5, 2016
Site: www.eurekalert.org

Researchers from the UCLA Department of Medicine, Division of Hematology Oncology and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have published two studies that define how key genetic factors affect blood-forming stem cells by either accelerating or hindering the cells' regenerative properties. The findings could one day lead to improved treatments for people undergoing common therapies for cancer such as chemotherapy and radiation. Blood-forming stem cells, or hematopoietic stem cells, are found in the bone marrow. These cells have two unique properties: They can self-renew and, through a process called differentiation, they can form any type of blood cell. A healthy immune system depends on the regenerative abilities of hematopoietic stem cells. Common cancer therapies such as chemotherapy and radiation can eliminate cancer by killing cancer cells. But these treatments also damage hematopoietic stem cells, which can impede the cells' ability to regenerate blood, slowing the immune system and resulting in a longer, more complicated recovery for people with cancer. Previous research indicated that certain genes may alter hematopoietic stem cells' regenerative capacity by either accelerating or hindering the cells' ability to restore the immune system, but more research was needed to pinpoint the specific genetic activity and effects. One of the new studies focused on a gene called Grb10 that is expressed by hematopoietic stem cells. Grb10's function was previously not known, so to better understand its role, the scientists deleted Grb10 from hematopoietic stem cells in lab dishes and in mice that had received radiation. They found that deleting Grb10 strongly promotes hematopoietic stem cell self-renewal and differentiation. In the other study, researchers analyzed a protein called DKK1. DKK1 is produced by a gene expressed by a specific "bone progenitor" cell that is present in the "niche," or cellular environment, that surrounds the hematopoietic stem cell. Typically, bone progenitor cells regenerate bone, but scientists had previously hypothesized that these cells also play an important role in regulating hematopoietic stem cells' ability to self-renew and differentiate into other blood cells. "The cellular niche is like the soil that surrounds the stem cell 'seed' and helps it grow and proliferate," said Dr. John Chute, professor of medicine in the Division of Hematology Oncology in the UCLA David Geffen School of Medicine and the study's senior author. "Our hypothesis was that the bone progenitor cell in the niche may promote hematopoietic stem cell regeneration after injury." The researchers showed that adding DKK1 to hematopoietic stem cells in lab dishes and mice that had received radiation produced a cascade effect within the cell niche that greatly enhanced hematopoietic stem cells' ability to self-renew and differentiate into other blood cells. Taken together, the studies uncover two molecular mechanisms that could potentially be manipulated to increase the regenerative properties of hematopoietic stem cells and improve cancer therapy. Scientists can now test drugs that inhibit Grb10 or test the effectiveness of administering DKK1 intravenously to promote immune regeneration in people who have received chemotherapy and radiation or those undergoing bone marrow transplants. Chute, who also is a member of the UCLA Jonsson Comprehensive Cancer Center, is the senior author of both papers. The first author of the Nature Medicine study is Heather Himburg and other authors are Mamle Quarmyne, Xiao Yan, Joshua Sasine, Liman Zhao, Grace Hancock, Jenny Kan, Katie Pohl and Evelyn Tran of UCLA; and Phuong Doan, Nelson Chao and Jeffrey Harris of Duke University. Other authors of the Cell Reports study are Yan, Himburg, Pohl, Quarmyne, Tran, Yurun Zhang, Tianchang Fang, Kan and Zhao of UCLA; and Doan and Chao of Duke University. The studies were published in the journals Nature Medicine (embargo lifts at 11:00 a.m. US Eastern time on Monday, December 5, 2016) and Cell Reports (published on November 1, 2016). The studies were funded by grants from the National Heart, Lung, and Blood Institute (HL-086998-05), the National Institute of Allergy and Infectious Diseases (AI-067798), a California Institute for Regenerative Medicine Leadership Award (LA1-08014), a National Institute of Allergy and Infectious Diseases' Centers for Medical Countermeasures Against Radiation Pilot Award (2U19AI067773-11), and by the UCLA Broad Stem Cell Research Center.


Wang J.-G.,Jilin University | Huang J.,University of California at Los Angeles | Chin A.I.,Broad Stem Cell Research Center
Asian Journal of Andrology | Year: 2014

To examine the outcomes of patients with high-risk prostate cancer (PCa) treated by robot-assisted radical prostatectomy (RARP) and evaluate the value of multi-parametric magnetic resonance imaging (MRI) in estimating tumor stage, extracapsular extension, and grade, and the application of nerve sparing (NS) techniques. Patient demographics, preoperative imaging, surgical parameters, pathological features, functional and recurrence outcomes were collected retrospectively in patients with high-risk PCa who underwent RARP between December 2009 and October 2013. Pathological whole mount slides to assess NS were compared with potency, recovery of continence, and surgical margins (SM). Forty-four cases of high-risk PCa were identified with a median followup of 24 months and positive surgical margins (PSM) rate of 14%. Continence returned in 86%, with potency rate of 58%. Of the 25 cases with a preoperative multi-parametric MRI, MRI improved clinical staging from 28% to 88%, respectively. Following risk stratification of NS by microscopic analysis of whole mount pathology, patients with Group A (bilateral NS), Group B (unilateral NS), Group C (partial NS), and Group D (non-NS) had 100%, 92%, 91%, and 50% continence rates, and 100%, 80%, 45%, and 0% potency rates, respectively, with an inverse correlation to PSM. RARP in men with high-risk PCa can achieve favorable oncologic and functional outcomes. Preoperative MRI may localize high-grade tumors and improve clinical staging. Extent of NS is influenced by clinical staging and may balance potency and continence with PSMs.


Ye L.,University of Sichuan | Ye L.,Broad Stem Cell Research Center | Fan Z.,Capital Medical University | Yu B.,Broad Stem Cell Research Center | And 6 more authors.
Cell Stem Cell | Year: 2012

Human bone marrow mesenchymal stem/stromal cells (MSCs) are multipotent progenitor cells with multilineage differentiation potentials including osteogenesis and adipogenesis. While significant progress has been made in understanding transcriptional controls of MSC fate, little is known about how MSC differentiation is epigenetically regulated. Here we show that the histone demethylases KDM4B and KDM6B play critical roles in osteogenic commitment of MSCs by removing H3K9me3 and H3K27me3. Depletion of KDM4B or KDM6B significantly reduced osteogenic differentiation and increased adipogenic differentiation. Mechanistically, while KDM6B controlled HOX expression by removing H3K27me3, KDM4B promoted DLX expression by removing H3K9me3. Importantly, H3K27me3- and H3K9me3-positive MSCs of bone marrow were significantly elevated in ovariectomized and aging mice in which adipogenesis was highly active. Since histone demethylases are chemically modifiable, KDM4B and KDM6B may present as therapeutic targets for controlling MSC fate choices and lead to clues for new treatment in metabolic bone diseases such as osteoporosis. © 2012 Elsevier Inc.


News Article | January 13, 2016
Site: www.biosciencetechnology.com

Scientists at the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have uncovered two specific markers that identify a stem cell able to generate heart muscle and the vessels that support heart function. This discovery may eventually aid in identifying ways to use stem cells to regenerate damaged heart tissue after a heart attack. Dr. Reza Ardehali, the study’s senior author, and his team published their findings in the journal Stem Cell Reports. “In a major heart attack, a person loses an estimated 1 billion heart cells, which results in permanent scar tissue in the heart muscle. Our findings seek to unlock some of the mysteries of heart regeneration in order to move the possibility of cardiovascular cell therapies forward,” said Ardehali, who is an associate professor of cardiology and a member of the UCLA Broad Stem Cell Research Center. “We have now found a way to identify the right type of stem cells that create heart cells that successfully engraft when transplanted and generate muscle tissue in the heart, which means we’re one step closer to developing cell-based therapies for people living with heart disease.” The method is still years away from being tested in humans, but the findings are a significant step forward in the use of human embryonic stem cells for heart regeneration. The research team used human embryonic stem cells, which are capable of turning into any cell in the body, to create cardiac mesoderm cells. Cardiac mesoderm cells have some stem cell characteristics, but only generate specific cell types found in the heart. The researchers pinpointed two distinct markers on cardiac mesoderm cells that specifically create heart muscle tissue and supporting vessels. They then transplanted these cells into an animal model and found that a significant number of the cells survived, integrated and produced cardiac cells, resulting in the regeneration of heart muscle and vessels. Ardehali, who is both a physician and a scientist, treats patients with advanced heart disease and also studies ways to cure or reverse heart disease. His goal is to one day be able to develop regenerative heart cells from stem cells and then transplant them into the heart through a minimally invasive procedure, replacing scar tissue and restoring heart function. Another study recently published by Ardehali and his team helps further this goal by outlining a novel approach to image, label and track transplanted cells in the heart using MRI, a common and non-invasive imaging technique. That study, which was published in the journal Stem Cells Translational Medicine, used specialized particles that are easily identified using an MRI. The labeling approach allowed Ardehali and his team to track cells in an animal model for up to 40 days after transplantation. The first author on both studies was Rhys Skelton, who was a visiting graduate student in Ardehali’s lab when he completed the research. Skelton has since completed his studies at the Murdoch Childrens Research Institute in Australia and received a Ph.D. from the University of Melbourne. He plans to return to UCLA as a postdoctoral scholar to continue his research on human embryonic stem cell-derived cardiac cells with the hope of one day developing a cell-based therapy for heart disease patients in need. “Our findings show, for the first time, that specific markers can be used to isolate the right kind of early heart cells for transplantation,” said David Elliott, a co-author of both studies, leader of the cardiac development research group at the Murdoch Institute and  Skelton’s doctoral supervisor. “Furthermore, our cell labeling and tracking approach allows us to determine the viability and location of transplanted cells.” Both studies were supported by the California Institute of Regenerative Medicine and the UCLA Broad Stem Cell Research Center.


News Article | September 1, 2016
Site: www.spie.org

Mitochondria are organelles that reside within cells. They are known as the cell's ‘powerhouse’ because they generate chemical energy in the form of adenosine triphosphate (ATP). Mitochondria are ∼2×1μm in size and contain their own genome, known as mitochondrial DNA (mtDNA), which is independent of the nuclear genome. mtDNA is essential for cell respiration and the production of ATP by a process called oxidative phosphorylation. mtDNA mutations can cause morbidity and mortality in humans, and there are currently no effective treatments or cures available for mtDNA diseases. The ability to transfer isolated mitochondria with a specific mtDNA sequence into target human cells would advance studies on cell metabolism and how mitochondria interact with their host cell, and also could lead to new therapeutic strategies to treat mtDNA-related disorders. There are few methods for transferring isolated mitochondria into mammalian cells.1 The most common approach is to fuse a donor cell that contains mitochondria with mtDNA of interest with a recipient cell devoid of mtDNA, also known as a ρ0 (rho-null) cell. The resulting cytoplasmic hybrid (or cybrid) cell contains the mtDNA from the donor cell and the nuclear DNA from the recipient cell. However, the cybrid also has a mixture of other cytosolic components such as mRNAs, proteins, lipids, and other organelles. The ‘cleanest’ method of transferring isolated mitochondria into cells is by microinjection. However, because tolerated pipette tips have a relatively small diameter, clogging and cargo damage often occur, which reduces efficiency. To transfer large, micrometer-sized cargo into mammalian cells, we have invented the photothermal nanoblade.2 We took a titanium-coated glass micropipette with a 3μm-inner-tip diameter and loaded it with isolated mitochondria. The pipette was placed adjacent to a cell membrane, and heated with a 532nm-wavelength non-damaging laser pulse. A transient vapor bubble in the surrounding aqueous culture media generated by rapid heat transfer caused a membrane incision by shear stress. This enabled active, pressure-driven cargo delivery of genetic material,3 conjugated quantum dots,4 and live intracellular bacterial pathogens5, 6 into mammalian cells with high efficiency and cell viability. Since bacteria and mitochondria are roughly the same size, we were able to isolate mitochondria from one cell line (MDA-MB-453) and transfer it into a different ρ0 cell line (143BTK−ρ0) using the nanoblade.7 ρ0 cells cannot survive in culture media deficient in uridine because respiration is required for cells to manufacture this essential nucleic acid building block (see Figure 1). Three cell clones, termed rescue 1–3, received mitochondria by nanoblade transfer and grew on media lacking uridine. The transferred mtDNA was replicated over time by the new host cell clones as they continued to grow (see Figure 2). We characterized the function of transferred mitochondria in the rescue cells. ATP concentrations were comparable with the mitochondrial donor cell and 143BTK parent cell (from which the ρ0 cell was generated). We also recovered respiration in rescue clones 1–3 to a level comparable with the mitochondrial donor and parent cell lines, and determined the expression of 33 nuclear-encoded metabolism-regulating genes, as well as levels of ∼100 small metabolites. Principal component analysis showed that rescue lines 1 and 3 were similar to the parent cell line in these key features, whereas rescue line 2 was most similar to the ρ0 recipient cells and not fully rescued. In other words, the transfer of mitochondria reset the metabolic profile of a ρ0 cell to that of the parent cell in most, but not all cases. This phenomenon left open questions related to the mechanism(s) of metabolic rescue. In summary, to enable studies of mitochondrial processes and to potentially provide a futuristic pathway for addressing mtDNA diseases, we outfitted a photothermal nanoblade to transfer isolated mitochondria into ρ0 cells to rescue their metabolic defects. Because the nanoblade transfers mitochondria to one cell at a time with an output of ∼100 cells/hour, we are developing a higher throughout method called a biophotonic laser-assisted surgery tool (BLAST) to transfer mitochondria into 100,000 cells/minute.8 A commercial prototype combining high-throughput delivery with ease-of-use features is now under development by the biotech start-up company NanoCav, LLC. With BLAST, we aim to improve our understanding of fundamental mitochondrial biology and also come closer to developing potential approaches to address mtDNA disorders. The authors acknowledge UC Discovery Biotechnology Award 178517, Air Force Office of Scientific Research FA9550-15-1-0406, NIH grants GM007185, GM114188, GM073981, GM061721, EB014456, CA009056, CA90571, CA009120, CA156674, CA185189, and CA168585, NSF grant CBET-1404080, CIRM grants RB1-01397 and RT3-07678, a Prostate Cancer Foundation Challenge Award, a Broad Stem Cell Research Center Training Grant and Innovator Award, and support from NanoCav, LLC. The authors thank K. Niazi and S. Rabizadeh (NantWorks, LLC). NantWorks, LLC has licensed the photothermal nanoblade and BLAST from the Regents of the University of California. Pei-Yu Chiou and Michael A. Teitell received sponsored research funding from NantWorks, LLC.

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