Newsletter - May 2014

CORD:USE
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Donate or Save - Take an Informed Decision
Donarlo o Guardarlo - Toma una Decisión Informada

Donarlo o Guardarlo pamphlet

Ted Goldberg Lerner, CEO, Cordón Vital

We report on a pioneer program in México City designed to educate expectant mothers about both cord blood donation and private storage, made possible by the cooperation, to mutual benefit, of public and private institutions.

Cordón Vital, a private (family) cord blood bank active in México City since 2001, together with Médica Sur Lomas Woman's Hospital, a private obstetric hospital (formerly Hospital Santa Teresa), formed an alliance in April 2007 with the public cord blood bank of the México Social Security Institute (IMSS) that was founded in 2005.

These three institutions launched a program called Donate or Save (Donarlo o Guardarlo) your newborn's cord blood. The alliance developed educational materials that encouraged new mothers to take an informed decision on the three options: Donate cord blood to a public bank, Save it in a family bank, or discard it.

The public bank IMSS contributed training to the medical and paramedical staff of the hospital, as well as the materials required for the assessment of donors and the collection of cord blood. The private bank Cordón Vital contributed the development and printing of the educational material, and coordinated the logistical and educational aspects of the program. This included the control of files and collection kits, the shipping and delivery to the IMSS cord blood bank, as well as additional education efforts with all participants in the chain of patient care. Médica Sur Lomas participated in the distribution of the educational material among their patients, the promotion of the altruistic donation among their pregnant patients and health professionals, and allowed the use of their facilities.

Donarlo o Guardarlo Program Heads Donarlo o Guardarlo Mom Assessment

Figure on the left shows the program heads from left to right: Dr. Angel Guerra, QFB Ruth Contreras, LAE Adriana Rivera, Dr. Jorge Kunhardt, and Ted Goldberg.
Figure on the right shows a mother going through assessment.

Between April 2007 and December 2012, 1264 expectant mothers who agreed to take part in the program (by signing an informed consent) were evaluated; and 800 units of cord blood from mothers who met the selection criteria were collected. Only 100 units were successfully cryopreserved and validated for their clinical use in transplantation at the IMSS centers. The remaining 700 collected units were not cryopreserved nor validated due to: incomplete medical records, lack of signature from the (collecting) physician responsible for the patient, insufficient volume collected (threshold volume was 80 ml) or insufficient cellularity (threshold TNC was 800 million).

Since then, out of the 100 successfully stored cord blood donations, 8 have been used for transplant: 6 for patients diagnosed with Acute Lymphoblastic Leukemia (3 children and 3 adults); 1 for a patient with Severe Aplastic Anemia; and 1 for a patient with Myelodysplastic Syndrome. Currently 2 more units have been found compatible with patients in need and are being evaluated for transplant.

According to annual reports from the World Marrow Donor Association (WMDA), the public cord blood bank of La Raza National Medical Center of the Méxican Institute for Social Security (IMSS) has been for the last few years among the top five banks world wide with the highest utilization rate of stored donations. Today, the IMSS cord blood bank provides service to seven IMSS transplant centers.

During the Donate or Save education campaign, both the public bank IMSS and the private bank Cordón Vital saw an increase in their enrollment from the participating hospital Médica Sur Lomas. This goes to show that when public and private cord blood banks work together towards better education of expectant parents, everyone benefits.

In January 2013, the General Health Law in México was amended by the Health Ministry to promote that all (public and private) Obstetric Attention Centers / Maternity Clinics must ask all pregnant women to consider donating their newborn's cord blood. For this reason, the three partner institutions, IMSS, Cordón Vital, and Médica Sur Lomas, are revising their education program in order to improve some aspects that may decrease the rejection rate of the donated units. The new slogan will be: "Your Newborn's Cord Blood - Take an informed decision".

Donarlo o Guardarlo LOGOS Participants
* Dr. Angel Guerra Márquez, MD; Cord Blood Bank Manager; Centro Medico Nacional La Raza (La Raza National Medical Center); Instituto Méxicano del Seguro Social - IMSS (Mexican Institute for Social Security)
* Dr. Jorge Kunhardt Rasch, MD; Medical Director; Médica Sur Lomas Woman's Hospital;
* L.A.E. Adriana Rivera Acosta; Patients and Physicians (Attention) Services; Médica Sur Lomas Woman's Hospital
* L.C. Juan Carlos Rodriguez Rivera; Hospital Management Deputy Director; Médica Sur Lomas Woman's Hospital
* QFB Ruth Contreras Rivera; Donate or Save Program Coordinator; Cordón Vital
* Ted Goldberg Lerner; CEO; Cordón Vital

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DHA Omega-3 Supplement in Mom's Diet Boosts Stem Cells in Baby's Cord Blood

Omega-3 capsules arranged in the shape of a fish

Irene Martini, Enea Gino Di Domenico, Roberta Scala, Francesca Caruso, & Herbert Valensise

(image courtesy of Seafood New Zealand)

Omega-3 fatty acids are called "essential" because they are required for a healthy metabolism. Humans and other mammals must ingest the simplest essential fatty acids in their diet, because their bodies cannot synthesize them. The best dietary source is fish oil. Docosahexaenoic acid (DHA) is a more complex fatty acid that our bodies can manufacture to a limited extent.

DHA is a primary structural component of the human brain, cerebral cortex, skin, sperm, testicles and retina. In young men, DHA levels tend to follow their diet, whereas young women and especially pregnant or lactating women manufacture higher levels of DHA [1]. Efforts to link DHA consumption with brain behaviors, such as ADHD in children or Alzheimer's Disease in older adults, are an active area of research.

Studies of whether DHA consumption during pregnancy helps babies have had mixed results. Some studies find that DHA supplements improve infant brain and eye development, or that they benefit preterm babies and mothers with post-partum depression. Olsen found that when expectant mothers consumed large quantities of fish, rich in DHA, there was an increase in the gestational age of their babies, a greater foetal weight at birth, and less incidence of pre-eclampsia during pregnancy [2].

The American Congress of Obstetricians and Gynecologists (ACOG) has no recommendation on the subject of DHA supplements during pregnancy, even though DHA is recommended by the U.S. Institute of Medicine (IoM) and the World Health Organization (WHO) [3]. Nonetheless, many individual doctors and dieticians encourage DHA consumption during pregnancy [4].

SmartBank has conducted a study of how DHA consumption during pregnancy impacts the stem cell concentration in newborn cord blood. Denburg et al. were the first to test this in a randomized study; they found that pregnant women who received fish oil capsules from gestation week 20 until delivery had a higher CD34+ percentage (a measure of stem cells) in their baby's cord blood [5].

The metabolic demand for DHA increases over the course of pregnancy, reaching peak during the third trimester. In line with this observation, the SmartBank trial enrolled two groups of participants: women at 20 and 28 weeks of gestation (40 and 64 expectant mothers, respectively). Each trial group was randomly divided between a study arm and a control arm. All of the participants ingested a daily oil capsule through week 40. On the study arm the capsules contained 250mg DHA, whereas the control arm received 250mg olive oil. The level of DHA in participant's blood was tested at the start of the study and at week 37-38.

Cord blood was collected from all of the babies delivered by mothers in the study, as well as a reference group of 44 deliveries at the same hospital. The stem cell count of the cord blood was tested by flow cytometry within 48 hours of collection.

Martini et al. DHA study results

As this figure shows, the SmartBank trial found that women who received DHA supplements had a significantly higher stem cell viability (measured by 7-AAD assay) in their cord blood than the control group. Moreover, the concentration of Total Nucleated Cells (TNC/ml) in their cord blood was correlated (not shown) with the concentration of DHA (%).

We conclude that this simple dietary supplement can help improve the yield of cord blood collections.

References

  1. Giltay EJ, Gooren L J G, Toorians AWFT, Katan MB, & Zock PL. Docosahexanoic acid concentrations are higher in women than in men because of estrogenic effects. Amer. J. Clin. Nutr. 2004; 80(5): 1167-1174. html
  2. Olsen SF & Secher NJ. A possible preventive effect of low-dose fish oil on early delivery and pre-eclampsia: indications from a 50 year old controlled trial. Br.J. Nutr 1990; 64(3):599-609 PMID:2265175
  3. Linda D. Bradley, MD, Beth Reardon, MS RD LDN, John M. Thorp, Jr. MD, Barbara A. Underwood, PhD, & Fernando E. Viteri, MD, ScD Clinical Update: Women's Health and Nutrition - Demographic Challenges Supplement to Ob. Gyn. News 2009 pdf
  4. Keli Hawthorne, Dietitian & Expert Author for BabyCenter.com Is it safe to take a fish oil or other omega-3 supplement during pregnancy? answer
  5. Denburg JA, Hatfield HM, Cyr MM, Hayes L, Holt PG, Sehmi R, Dunstan JA & Prescott SL. Fish Oil Supplementation in Pregnancy Modifies Neonatal Progenitors at Birth in Infants at Risk of Atopy 2005; Pediatric Research 57:276-281; doi:10.1203/01.PDR.0000148279.72611.1D PMID:24232253.

Irene Martini, PhD, is the founder and CEO of SmartBank, the first family cord blood bank in Italy. Francesca Caruso also works for SmartBank as a nutritionist. Enea Gino Di Domenico, PhD, is a post-doctoral fellow in the Department of Biology and Biotechnology at Sapienza University of Rome. Roberta Scala, MD, is a gynecologist at Ospedale FateBeneFratelli in Rome. Herbert Valensise, MD, is a professor at University Tor Vergata and a gynecologist at Ospedale FateBeneFratelli, in Rome.

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Storage of Mesenchymal Stem/Stromal cells in family stem cell banks: What do they offer?

Pedro Silva Couto

Pedro Silva Couto, Instituto Superior Técnico, Portugal

Mesenchymal stem/stromal cells (MSC) are being widely studied in research and in clinical trials. Their useful properties include the ability to modulate the patient's immune system, promote cell growth, and to differentiate into more specialized cell types. This amazing potential has been explored in a large scope of diagnoses such as graft versus host disease (GvHD), rheumatoid arthritis, cardiomyopathy, liver cirrhosis, Alzheimer's, spinal cord injury, chronic wounds, and diabetes among many others [1,2].

In 2013 more than 5600 articles were published (accessed via PubMed) with MSC as main subject, and during the present year around 1000 papers were already published under the same subject. Demonstrating the medical potential around MSC, 372 clinical trials are ongoing and 17% of them use umbilical cord tissue (UC) as the only MSC source (see Figure).

Pie chart of MSC sources used in clinical trials March 2014

Figure 1: MSC sources listed on ClinicalTrials.gov during March 2014. Keyword search criteria were: umbilical cord blood (UCB), umbilical cord (UC), adipose tissue (AT), bone marrow (BM), placenta, and mesenchymal stem cells. The group named "others" includes MSC from endometrium, synovium and dental pulp.

Since the number of MSC decreases with a person's age [3], neo-natal sources such as umbilical cord blood (UCB), umbilical cord tissue (UC), or placenta are being studied to replace adult ones such as bone marrow (BM), adipose tissue (AT) or dental pulp (DP).

The isolation of MSC from neo-natal sources have several advantages over adult sources: the procedure is completely non-invasive and has high success rates associated [4,5]. Moreover recent studies indicate that MSC collected from neo-natal sources have higher proliferative abilities than MSC isolated from adult ones [6].

Many stem cell banks around the world now offer the service of collecting MSC from umbilical cord tissue. Despite being technically possible, the storage of MSC from cord blood is not commercially offered because the isolation rates are really low [7]. From a stem cell bank point of view, cord blood is stored exclusively due to its content of blood-forming (hematopoietic) stem cells, and cord tissue is stored due to its MSC content.

When family cord blood banks offer the service of storing MSC from umbilical cord tissue (UC), they are not always selling the same thing. This is an area where most parents are completely unaware of the differences in laboratory procedures and the medical potential of the final product.

Within the family-oriented stem cell bank context, three main services are being offered nowadays: (1) Full or segmented cord storage, (2) Explants processing, and (3) Digestion processing. As the processing and storage methods have a major impact on the quantity and quality of the cellular yield [8-10], it is extremely important for parents to have full knowledge around what type of services are being offered.

The simplest service available is Full/segmented Cord Storage. The umbilical cord is collected at birth, washed several times at the lab, immersed within an appropriate solution carrying a cryoprotectant agent, and then cryopreserved. The cryoprotectant agents are molecules that protect tissues and cells from freezing damages. Sometimes the cord is cut into segments, but it is basically the same procedure. With Full/segmented Cord Storage, MSC are not isolated from the cord. The hope is that they can someday be retrieved from the cord tissue with good cell yield and viability.

There are two basic methods for processing the umbilical cord tissue to isolate the MSC: the Explants method or the Digestion method.

The Explants method starts by mincing the umbilical tissue into tiny pieces and growing them in a culture medium. This allows the MSC to be isolated because they adhere to the surface of the culture dishes. However, it is important to know that most stem cell banks do not fully perform the cell isolation with Explants method. After mincing the cord into pieces, they do not wait for cells to culture and adhere, instead the cord pieces are placed in a cryoprotectant agent and immediately cryopreserved. Under these conditions the explants processing is quite similar to the Full/segmented storage.

The Digestion method relies on the action of enzymes to break up the collagen matrix of the cord tissue. The enzyme digestion is followed by several steps to wash, filter, and centrifuge the separated cells. This method results in a solution that carries fully isolated MSC. The solution is then cryopreserved. At the end of Digestion processing the cells are completely ready for further operations, if needed.

The Table summarizes the available UC-MSC storage services for parents. From a stem cell bank perspective, Full/segmented cord storage as well as Explants processing service are both quite simple and fast [11], and have a low level of "substantial manipulation" (to quote FDA terminology) [12]. The digestion processing is more prolonged, requires many steps, and has a higher degree of manipulation because of the use of enzymatic solutions. The reagents in the digestion method are also more expensive. However, a parent perspective should be about quality control, and when the MSC are not isolated, it is difficult to know their number, identity, and viability or proliferation properties. Only in Digestion processing do we know how many cells of what quality were harvested.

Table: Comparison of UC-MSC storage offered in stem cell banks

Characteristics Full/segmented Cord Explants Processing Digestion Processing
State of MSC MSC trapped in UC MSC trapped in UC MSC fully isolated
Time consuming Lower Lower Higher
Technical difficulty Lower Lower Higher
Degree manipulation Lower Lower Higher
Process Cost Lower Lower Higher
Quality control Harder Harder Easier
Integration of process Harder Harder Easier

Summarizing, parents should be aware that, before they can be used in clinical trials, the cryopreserved MSC will have to be further processed after thaw for patient application. Only in Digestion processing do we truly know the cell count, cell properties, and cell viability of the MSC. In Full/segmented cord storage and Explants processing, the MSC are still entrapped within the cord pieces, requiring additional effort post-thaw to isolate the MSC. But even if parents choose the Digestion processing, their cells are still not treatment-ready. Since the number of cells required for MSC therapy is high (usually ranging between 1-6 millions of MSC per Kg of patient's body weight) the MSC collected during the isolation processes are not enough [13] and need always to be expanded in the laboratory before treatment.

Parents who wish to store MSC from cord tissue should look at exactly what kind of services are being offered by the stem cell banks, how they perform the quality control tests, and ultimately what kind of guarantees they offer in case of the sample is released for transplantation purposes.

Pedro Silva Couto recently obtained his Master of Science degree in biological engineering from Instituto Superior Técnico (IST), Portugal. During the last year he was performing his master thesis at Crioestaminal S.A., the biggest stem cell bank in Portugal. The main subject focused during his thesis was the human umbilical cord matrix mesenchymal stem cells isolation methods from a stem cell bank perspective. Currently Pedro is looking for new research projects within stem cell technologies to pursue his career.

References

  1. R.C. Schugar, S.M. Chirieleison, K.E. Wescoe, B.T. Schmidt, Y. Askew, J.J. Nance, J.M. Evron, B. Peault, and B.M. Deasy, High harvest yield, high expansion, and phenotype stability of CD146 mesenchymal stromal cells from whole primitive human umbilical cord tissue J. Biomed. Biotechnol. 2009:789526, Jan. 2009
  2. R.R. Taghizadeh, K.J. Cetrulo, and C.L. Cetrulo, Wharton's Jelly stem cells: future clinical applications Placenta, 32(4):S311-5, Oct. 2011.
  3. A.I. Caplan, Why are MSCs therapeutic? New data: new insight J. Pathol. 217(2):318-24, Jan. 2009.
  4. C. De Bruyn, M. Najar, G. Raicevic, N. Meuleman, K. Pieters, B. Stamatopoulos, A. Delforge, D. Bron, and L. Lagneaux, A rapid, simple, and reproducible method for the isolation of mesenchymal stromal cells from Wharton's jelly without enzymatic treatment Stem Cells Dev., 20(3):547-57, Mar. 2011.
  5. C.-Y. Fong, A. Subramanian, A. Biswas, K. Gauthaman, P. Srikanth, M. P. Hande, and A. Bongso, Derivation efficiency, cell proliferation, freeze-thaw survival, stem-cell properties and differentiation of human Wharton's jelly stem cells Reprod. Biomed. Online, 21(3):391-401, Sep. 2010.
  6. R. Hass, C. Kasper, S. Böhm, and R. Jacobs, Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC Cell Commun. Signal. 9(1):12, Jan. 2011.
  7. M. Secco, E. Zucconi, N.M. Vieira, L.L.Q. Fogaça, A. Cerqueira, M.D.F. Carvalho, T. Jazedje, O.K. Okamoto, A.R. Muotri, & M. Zatz, Multipotent stem cells from umbilical cord: cord is richer than blood! Stem Cells, 26(1):146-50, Jan. 2008.
  8. A. Iftimia-Mander, P. Hourd, R. Dainty, and R.J. Thomas, Mesenchymal Stem Cell Isolation from Human Umbilical Cord Tissue: Understanding and Minimizing Variability in Cell Yield for Process Optimization Biopreserv. Biobank., 11(5):291-298, Oct. 2013.
  9. P. Salehinejad, N.B. Alitheen, A.M. Ali, A.R. Omar, M. Mohit, E. Janzamin, F.S. Samani, Z. Torshizi, and S.N. Nematollahi-Mahani, Comparison of different methods for the isolation of mesenchymal stem cells from human umbilical cord Wharton's jelly In Vitro Cell. Dev. Biol. Anim. 48(2):75-83, Feb. 2012.
  10. Y.-F. Han, R. Tao, T.-J. Sun, J.-K. Chai, G. Xu, and J. Liu, Optimization of human umbilical cord mesenchymal stem cell isolation and culture methods Cytotechnology 51, Jan. 2013.
  11. A. Petsa, S. Gargani, A. Felesakis, N. Grigoriadis, and I. Grigoriadis, Effectiveness of protocol for the isolation of Wharton's Jelly stem cells in large-scale applications In Vitro Cell. Dev. Biol. Anim. 45(10):573-6, Dec. 2009.
  12. The Parliament Council of the Union, Regulation (EC) No.1394/2007 of the European Parliament and of the Coucil of 13 November 2007 no. 1394, 2007.
  13. N. Tsagias, I. Koliakos, V. Karagiannis, M. Eleftheriadou, and G.G. Koliakos, Isolation of mesenchymal stem cells using the total length of umbilical cord for transplantation purposes Transfus. Med. 21(4):253-61, Aug. 2011.