Dr. Espinosa's research is focused on understanding the repair of Central Nervous System (CNS) damage caused by disease or injury. The principal research deals with the role of oligodendrocytes, the cells that synthesize and maintain myelin in the central nervous system. These studies use two animal models of myelin deficiency to investigate mechanisms of remyelination and to study techniques for promoting remyelination. The first animal model, the rat myelin deficient mutant (md rat), displays extensive dysmyelination due to a mutation in the proteolipid gene (PLP), which is responsible for producing the most abundant protein in myelin. These animals live 24 days before succumbing to tremors and seizures. Healthy oligodendrocyte progenitors were implanted into the brain of these animals. We were able to assess cell migration, maturation and functional integration of grafted cells in the md host brain. Studies on host/graft interaction and ultrastructure would not have been possible without these mutant rats that offered us the advantage of working in an environment without inflammation and cell death, features associated with experimentally induced demyelination. The second animal model is a transgenic mouse overexpressing the PLP gene "4e". These animals are born and myelinate normally but their CNS starts to demyelinate around four months of age. Demyelination progresses and leads to hind limb impairment. With special attention, these animals live over one year. We use this animal model for two purposes:

1. To examine the improvements obtained when non-transgenic oligodendrocytes are grafted into the brain of these hosts. We showed that grafted cells survive, migrate to areas where naked axons are found and myelinate them.
2. To test the efficacy of treatments designed to stimulate endogenous neural stem cells to become myelin forming cell and remyelinate host axons. At the present time we are evaluating the neurological improvements obtained when these animals receive a single injection of a compound characterized in our laboratory. Our data have shown the activation of new oligodendrocytes that remyelinate demyelinated axons allowing the recovery of hind limb function in treated mice. These results are promising and we continue to use this transgenic mouse model to unravel the mechanisms of action of our compound in question. This approach to remyelination can be used after trauma and other conditions that lead to demyelination. This work has been and continues to be performed in collaboration with Dr. K. Ikenaka.

A second area of investigation includes understanding how to promote and sustain the inherent potential of the spinal cord to regenerate. This work is being performed in collaboration with Dr. S. Woerly, who devised a gel with properties resembling the embryonic CNS. Using this approach we have demonstrated axonal elongation across the lesion, migration of neurons into the gel and myelination. The properties of this gel prevented the formation of a gliotic scar yet allowed survival of astroglial cells that are known to provide trophic support. At present we are investigating the contribution of endogenous neural stem cells to the reconstruction of the spinal cord. During the past decade, we demonstrated that oligodendrocytes have a dual function in the CNS: myelination, and preservation of iron homeostasis. Therefore, part of our research efforts focus on assessing how iron metabolism is involved in dys- and de-myelinating diseases. In collaboration with the Pasteur Institute we are studying how the over-expression of the human transferrin gene in the brain affects myelination.

Dr. Espinosa has migrated into an innovative field of research, she has pioneered the use of simulated microgravity on neural stem cells and oligodendrocytes showing that in microgravity these cells proliferate more rapidly and with a concomitant shortening of the cell cycle. Moreover, when these cells were placed back in 1G they continued to proliferate more than the control cells maintained in 1G, as if these cells remembered having been in microgravity. These cells also showed increased migration as reported in Espinosa et al., 2013. She continued characterizing the behavior of oligodendrocytes in microgravity and revealed a fast and extensive and enhanced secretion of fatty acids and complex lipids as reported (Espinosa et al., 2016).

Dr. Espinosa obtained a NASA award in 2014 in preparation for space flight of her cells. Integration of the flight will take place at the Kennedy Space Center, at Cape Canaveral, to implement the flight of human neural stem cells and oligodendrocytes to the International Space Station (ISS), where the cells will remain for 30 days. Careful examination of the samples may reveal if the impact of real microgravity compares to simulated microgravity.

GRADUATE STUDENTS
Approaching Oligodendrocytes Development In Vivo and In Vitro

Mr. M. Aimie (1988-1991) - Grafts of premyelinating oligodendrocytes into post-natal 16 rat pups.

Ms. A. Watabe (spring quarter1992) rotation student. Migration of tumor cells in the rat brain Parenchyma.

Ms. Megan Wyeth (spring quarter 2006) rotation student. Contribution to the characterization of TS1 on a mouse model of Excitotoxicity.

Mr. Warin Krityakiarana (2006-2009). Effects of exercise on the intact adult spinal cord: implication for spinal cord repair.

SUMMER STUDENTS

Mr.Soeil, A. (1987) - Comparison of two cell culture systems for the study of oligodendroglia: Immunocytochemical study.

Mr. Mark, M. (1990) - Effect of Hexacosanol on post-natal CNS development.

CARE STUDENTS

Ms. Norma Sosa (1997and 1998) - Effect of Tf injections in the contralateral hemisphere of the md rat brain. Participated on the Characterization of spinal cord repair post-trauma.

Mr. Gamaliel Lorenzo (1999-2000) - Comprehensive analysis of the effect of basic fibroblast growth factor in the CNS.

Ms. Desiree Salazar (1999) - Participated on the analysis of the effect of IGF-1 in the CNS.

Mr. Wole Awosika (2000-2002) - Comprehensive characterization of the effect of IGF-1 on OL gene Expression (ongoing project).

Ms. Julie Garchow ( September 2001-June 2001)

Ms. Chioma Agbo (September 2001-)

SRP & 199 PROGRAM STUDENTS: Analysis of the effect of intraparenchymal injections of trophic factors in rodents

Mentor for the UC-LEADS Program

Mr.Johnny Garcia

Founder and Organizer of the First International Basic Neurochemistry School

held in Cordoba, Argentina (September 1st to 3rd, 2001)

NATIONAL and INTERNATIONAL COLLABORATORS

Dr. Jacques Borg. Univ. Louis Pasteur Faculty of Pharmacology, Strasbourg, France. Effect of Hexacosanol on neural cells in culture (1989-1992).

Dr. Daniele Condorelli. Univ. of Catania. Transferrin gene regulation in cultured neural cells chick and rat (1988-1990).

Dr. A. Shahar - Rat neuronal cultures. Electronmicroscopy 1988-1990).

Dr. M. Teresa Ramacci. Pharmaceutical Sigma Tau, Rome, Italy (1990-1994).

1. Effect of Acetyl-L-Carnithine on neural cells in culture.
2. Effect of Acetyl-L-Carnithine on myelin deficient rat pups.

Dr. Julian N. Kanfer. University of Manitoba, Canada.

1. Activity of a new myelin related enzyme "glycerophosphorylcholinephosphocholine phosphodiesterase (GPC) in cultured glial cells and dysmyelination rodent mutants (1989-1992).
2. Developmental expression of myelin Enzymes by developing oligodendroglia in different chemically defined media (1992-1999).

Dr. Pierre Rouget, College de France, Paris France. Behavior of immortalized oligodendrocytes, survival and migration (1990-1992).

Dr. Mario Zakin. Inst. Pasteur; Paris, France (1992-2003).

1. Analysis of brain specific expression of the human transferrin gene (HTF).
2. Comparison of transcription elements involved in HTF-gene regulation in wild type oligodroglia vs. an immortalize oligodendroglial cell line "CG4".
   Are the nuclear factors different?
3. Characterization of H-Tf transgenic mice.

Dr. Kazuhiro Ikenaka, Intl'. Inst. of Physiological Sciences. Okazaki, Japan (1997-present). Transplantation of cells of the oligodendroglial lineage into the demyelinated heterozygous PLP transgenic mouse: potential for repair.

Dr. Stephan Worely, Organogel Canada LT. Quebec, Canada (1998-present).

1. New insights on the repair of the injured cat spinal cord.
2. Enhancing edogenous spinal cord repair.

Dr. Pierre Gressens, INSERM U 676 & Service de NeuropediatrieHopital Robert Debre. Paris, France (2005-present). Neuroprotection by TS1 from NMDA excytotoxicity.

Dr. John Edmond, MRRC, UCLA (1998-present). Effect of carbon monoxide on the developing CNS.

Dr. Milan Fiala, MD, UCLA Orthopedic Hospital (2005-present).

1. Phagocytosis of amyloid-beta and the innate immunity in Alzehimer's disease.
2. Amyloid beta uptake by macrophages of Alzheimer's disease patients and cucuminoids.

Dr. Fernando Gomez-Pinilla, UCLA (2000-present). Effect of exercise on the intact adult spinal cord: implications for neural repair.

MITSUBISHI HEAVY INDUSTRIES, Ltd. Space Systems Designing Section. (2008-present) Propagation and commitment of neural progenitors in microgravity.

Dr. A. Feria Velasco, MD, PhD, Universidad de Guadalajara, Jalisco (2009-2016). Interventions to mitigate excitotoxicity in periventricular leukomalacia in a perinatal mouse model.

Dr. Carlos Cepeda, UCLA, (2004-present). In vivo trophic support in the excitotoxic environment

Dr. Raul C. Baptista, Genó mica Funcional y Diagnó stico Molecular, Departamento de Bioingenierías. Campus Guadalajara Tec de Monterrey. Impacto de microgravedad inducida sobre la expresió n genó mica en células progenitoras de sistema nervioso en cultivo celular.

SELECTED PUBLICATIONS

Espinosa de los Monteros, A; Baba, H; Zhao, P M; Pan, T; Chang, R; de Vellis, J; and Ikenaka, K. (2001) Remyelination of the Adult Demyelinated Mouse Brain by Grafted Oligodendrocyte Progenitors. J. of Neurochem. Res. Vol. 26:6, 673-682.

Espinosa-Jeffrey, Sara Becker-Catania Paul M Zhao, R. Cole, and J de Vellis. (2002) Phenotype Specification and Development of Oligodendrocytes and Neurons from Rat Stem Cell Cultures Using two Chemically Defined Media. Special Issue on Stem cells, J. Neurosci. Res. 69:810-825.

Saleh, MC; Espinosa de los Monteros, A; de Arriba Zerpa, G A; Fontaine, I; Piaud, O; Djordjijevic, D; Baroukh, N; Garcia Otin, A L; Ortiz, E; Lewis, S; Fiette, L; Santambrogio, P; Belzung, C; Connor, J R; de Vellis, J; Pasquini, J M; Zakin, M M; Baron, B; Guillou, F. (2003) Myelination and motor coordination are increased in transferrin transgenic mice. J Neurosci. Res. 1;72(5):587-94.

López, I; Zhao, P M; Yamaguchi, M; de Vellis, Jean; Espinosa-Jeffrey, A. (2004) Stem/progenitor cells in the postnatal inner ear of the GFP-nestin transgenic mouse. Int J Dev Neurosci 22,205-213.

StéphaneWoerly, Van Diep Doan, Norma Sosa, Jean de Vellis, and Araceli Espinosa-Jeffrey. (2004) Prevention of gliotic scar formation by NeuroGel (TM) allows partial endogenous repair of transected cat spinal cord, J. Neurosci. Res. (75):262-272.

Woerly, S; Awosika, O; Zhao, P; Agbo, C; Gomez-Pinilla, F; de Vellis, J; and Espinosa-Jeffrey, A. (2005) Expression of Heat Shock Protein (HSP)-25 and HSP-32 in rat spinal cord reconstructed with Neurogel^TM. Neurochem. Res. 30:721-35.

Espinosa-Jeffrey, A; Zhao, P; Awosika, A; Wu, N; Macias, F; Cepeda, C; Levine, M; & de Vellis, J. (2006) Activation,proliferation and commitment of endogenous, stem/progenitor cells to the oligodendrocyte lineage by a combination of neurotrophic factors in a rat model of dysmyelination. Develop. Neurosci., 28:488-498.

A. Espinosa-Jeffrey. (2007) Los Oligodendrocitos, las Celulas que Forman la Materia Blanca. In: Investigación en Neurociencias, Dr. Alfredo Feria Velasco; Homenaje a Científicos Mexicanos. Ruth De Celis, Bios Medica RDs. Zapopan, Jal. Vol. 2, pp 33-44.

N Chattopadhyay, A Espinosa-Jeffrey, J Tfelt-Hansen, S Yano, S Bandyopadhyay, EM Brown, J de Vellis. (2008) Calcium receptor expression and function in oligodendrocyte commitment and lineage progression: Potential impact on reduced myelin basic protein in CaR-null mice. J Neurosci Res 1;86 (10)2159-67. [PMID: 18438915].

Justin Zaghi, Ben Goldenson, Mohammed Inayathullah, Albert S. Lossinsky, Ava Masoumi, HripsimeAvagyan, Michelle Mahanian, Michael Bernas, Martin Weinand, Mark J. Rosenthal, Araceli Espinosa-Jeffrey, Jean de Vellis, David B. Teplow, Milan Fiala. (2009) Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy. Acta Neuropathol 117:111-124. DOI 10.1007/s00401-008-0481-0.

Masoumi, A., Goldenson, B., Ghirmai, S. Avagyan, H., Zaghi, J. Ken, A., Zheng, X., Espinosa-Jeffrey, A., Mhanian, M., Liu, P., Hewison, M., Mizwicki, M., Cashman, J., Fiala, M. (2009) 1α,25-dihydroxyvitamin D3 interacts with curcuminoids to stimulate amyloid-β clearance by macrophages of Alzheimer disease patients. Journal of Alzheimer's Disease 17, 703-717. DOI 10.3233/JAD-2009-1080.

Espinosa-Jeffrey A, Wakeman DR, Kim SU, Snyder EY, de Vellis J. (2009) Culture system for rodent and human oligodendrocyte specification, lineage, progression and maturation. CurrProtoc Stem Cell Biol. Sep;Chapter 2:Unit 2D.4. PMID: 19725014.

Espinosa-Jeffrey A, Hitoshi S, Zhao P, Awosika O, Agbo C, Olaniyan E, Garcia J, Valera R, Thomassian A, Chang-Wei R, Yamaguchi M, de Vellis J, Ikenaka K. (2010) Prospects for the use of stem cells in myelin repair. Published Online: Feb 19, 2010. DOI: 10.1002/jnr.22379; PMID: 20127853.

Krityakiarana, W; Espinosa-Jeffrey, A; Ghiani, C; Zhao, M; P. N. Topaldjikian; Gomez-Pinilla, F; Yamaguchi, M; M Kotchabhakdi and J. de Vellis. (2010) Voluntary Exercise Increases Oligodendrogenesis in Spinal cord. Int. Jour. of Neurosci. 120(4):280-90.

Araceli Espinosa-Jeffrey, Socorro A. R. Barajas, Alfonso R. Arrazola, Alana Taniguchi, Paul M. Zhao, PayamBokhoor, Sandra M. Holley, Don P. Dejarme, Brian Chu, Carlos Cepeda, Michael S. Levine, Pierre Gressens, Alfredo Feria-Velasco and Jean de Vellis (2013). White Matter Loss in a Mouse Model of Periventricular Leukomalacia Is Rescued by Trophic Factors. Brain Sci., 3 (4), 1461-1482; doi:10.3390/brainsci3041461.

Espinosa-Jeffrey A, Paez PM, Cheli VT, Spreuer V, Wanner I, et al. (2013). Impact of Simulated Microgravity on Oligodendrocyte Development: Implications for Central Nervous System Repair. PLoS ONE 8(12): e76963. doi:10.1371/journal.pone.0076963.

Krityakiarana, P.M. Zhao, K Nguyen, F. Gomez-Pinilla, N. Kotchabhakdi, Jde Vellis, A. Espinosa-Jeffrey (2016). Proof-of Concept that an Acute Trophic Intervention After Spinal Cord Injury Provides an Adequate Niche for Neuroprotection, Recruitment of Nestin Expressing Progenitors and Regeneration. Neurochemical. Res. 41 (1) pp 431-449.

A. Espinosa-Jeffrey, R. A. Arrazola, B. Chu, A. Taniguchi, S. M. Barajas, P. Bokhoor, J. Garcia, A. Feria-Velasco, J. de Vellis (2016). Trophic Factors Intervention Regenerate Nestin Progenitors in a Model of Perinatal BrainInjury. Integr Mol Med. 3(3):703-715.

Espinosa-Jeffrey A, Nguyen K, Kumar S, Toshimasa O, Hirose R, Reue K, Vergnes L, Kinchen J, Vellis J. (2016). Simulated microgravity enhances oligodendrocyte mitochondrial function and lipid metabolism. J Neurosci Res. 2016 Sep 28. doi: 10.1002/jnr.23958. [Epub ahead of print] PMID: 27680492

Espinosa-Jeffrey A. Physiologically-Relevant Cellular Models for Biomarkers and Drug Discovery. Ann Stem Cell Res Ther. 2018;2(2):1014. Epub 2018 Apr 26.

Hirose-Ikeda Megumi, Chu Brian, Zhao Paul, Akil Omar, Escalante Elida, Vergnes Laurent, Cepeda Carlos, Espinosa-Jeffrey Araceli (2020). Trophic factors are essential for the survival of grafted oligodendrocyte progenitors and for neuroprotection after perinatal excitotoxicity. 15( 3) 557-568. PMID: 31571668

Cepeda C., Vergnes L., Carpo N., Schibler M.J., Bentolila L.A., Karouia F., and Espinosa-Jeffrey A. (2019). Human Neural Stem Cells Flown into Space Proliferate and Generate Young Neurons. Appl. Sci. 9(19), 4042; https://doi.org/10.3390/app9194042 PMID: 34484810Sophia Shaka, Nicolas Carpo, Victoria Tran, and Araceli Espinosa-Jeffrey. (2020).” Behavior of Astrocytes Derived from Human Neural Stem Cells Flown onto Space”. Appl. Sci. 2021, 11(1), 41; https://doi.org/10.3390/app11010041.

Shaka S, Carpo N, Tran V, Ma YY, Karouia F.; Espinosa-Jeffrey A. (2021). Human Neural Stem Cells in Space Proliferate more than Ground Control Cells: Implications for Long-Term Space Travel." J Stem Cell Res Dev Ther 7: 069., Jan-2021

Shaka Sophia, Carpo Nicolas, Tran Victoria, Cepeda Carlos, Espinosa-Jeffrey Araceli. (2021). Microgravity Significantly Influences Neural Stem Cells Size and Numbers: Implications for Long-term Space Missions. Journal of Stem Cells Research, Development & Therapy. 7. 1-9. 10.24966/SRDT-2060/100088.

Biancotti JC, Carpo N, Zamudio J, Vergnes L, Espinosa-Jeffrey A (2022) Profiling the Secretome of Space Traveler Human Neural Stem Cells. J Stem Cell Res Dev Ther 8: 094.

Tran, V.; Carpo, N.; Shaka, S.; Zamudio, J.; Choi, S.; Cepeda, C.; Espinosa-Jeffrey, A. Delayed Maturation of Oligodendrocyte Progenitors by Microgravity: Implications for Multiple Sclerosis and Space Flight. Life 2022, 12, 797. https://doi.org/10.3390/life12060797