Do Cryopreserved Mesenchymal Stromal Cells Display Impaired Immunomodulatory and Therapeutic Properties?

Moll, Guido; Alm, Jessica J.; Davies, Lindsay C.; Bahr, Lena von; Heldring, Nina; Stenbeck-Funke, Lillemor; Hamad, Osama A.; Hinsch, Robin; Ignatowicz, Lech; Locke, Matthew; Lönnies, Helena; Lambris, John D.; Teramura, Yuji; Nilsson‐Ekdahl, Kristina; Nilsson, Bo; Blanc, Katarina Le

doi:10.1002/stem.1729

Cited by 306 publications

(294 citation statements)

References 43 publications

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“…In support of this, we have found that thawing induces 29) . This is the first translational evidence, which demonstrate the clinical benefit of using fresh MSCs .…”

Section: Mscs Display Impaired Responsiveness To Ifnγ Stimulationsupporting

confidence: 71%

Defining mesenchymal stromal cells responsiveness to IFN^|^gamma; as a surrogate measure of suppressive potency

Chinnadurai

Galipeau

2014

Inflammation and Regeneration

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“…In support of this, we have found that thawing induces 29) . This is the first translational evidence, which demonstrate the clinical benefit of using fresh MSCs .…”

Section: Mscs Display Impaired Responsiveness To Ifnγ Stimulationsupporting

confidence: 71%

Defining mesenchymal stromal cells responsiveness to IFN^|^gamma; as a surrogate measure of suppressive potency

Chinnadurai

Galipeau

2014

Inflammation and Regeneration

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“…3,33,34 In contrast, other studies 10,[35][36][37] have demonstrated that cryopreserved MSC exhibit equivalent viability and immunosuppressive potential to freshly isolated MSC from cell culture. Consistent with these findings, we found that freeze-thawed MEP displayed a viability of 95% and retained the ability to effectively suppress lymphocyte proliferation in vitro.…”

Section: Discussionmentioning

confidence: 93%

Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey

et al. 2016

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© Ferrata Storti Foundation IntroductionSince the first clinical trial of mesenchymal stromal cells (MSC) 9,10 Another important issue regarding the clinical application of MSCs is their culture under serum-free conditions. The majority of clinical studies have used MSCs that were expanded in media supplemented with fetal bovine serum (FBS). 1,[11][12][13][14][15] To avoid the risks associated with the use of FBS, 16 platelet lysate (PL) was proposed as a supplement to tissue culture media for MSCs. 17 Recently, several studies showed that MSCs that were expanded in PL exhibited the same efficacy as MSCs cultured in serum-containing media for the treatment of GvHD. 18-22To date, clinical studies have used MSCs that have been generated from several individual donors. Considering the aforementioned inter-donor heterogeneity and the need for a large number of "off-the-shelf" MSCs, the establishment of MSC banks appears to be an indispensable strategy for providing a continuous supply of MSCs with predictable potency. To our knowledge, there are few established MSC banks worldwide, and these MSC banks were generated by separately isolating, expanding, and freezing MSCs from up to 10 donors in FBS-containing media. [23][24][25][26] In the current study, we report for the first time the establishment of a serum-free and GMP-compliant MSC bank generated from pooled bone marrow mononuclear cells (BM-MNCs) of multiple donors as a novel strategy to circumvent donor-to-donor variability. Clinical-grade MSC endproducts (MEPs) derived from the MSC bank were thoroughly assessed for their proliferation, differentiation, and, in particular, for the allosuppressive potential in vitro. Importantly, 81 MEPs were administered as a rescue therapy to 26 pediatric patients with severe steroid-refractory aGvHD in seven transplantation centers. Safety and efficacy of MEPs was compared to MSCs generated from a single or several individual donors that have been used in the GvHDclinical studies reported thus far. Methods Generation of MSC bank and clinical-grade MEPsBone marrow was collected from 8 healthy volunteers (age 21-45 years old) after written informed consent and after the approval of the local Ethics Committee (n. 275/09). BM-MNCs were enriched from the bone marrow aspirate by using the Sepax II NeatCell process (Biosafe, Eysins, Switzerland) and frozen individually. After thawing and washing these BM-MNCs were pooled. This pool of BM-MNCs from 8 donors was used to generate MSCs over 14 days in culture. After their detachment, passage 1 mesenchymal stromal cells (MSC-P1) were washed and aliquoted into 209 cryovials (each containing 1.5x10 6 MSC-P1). Cryopreserved vials with MSC-P1 were referred to as the MSC bank.To generate clinical-grade MEPs, MSC-P1 aliquots from the MSC bank were thawed and after washing they were expanded in medium containing 10% PL till the end of passage 2. These MSCs were re-suspended in cryomedium (0.9% NaCl containing 5% HSA and 10% DMSO), distributed in cryobags (each containing 1-3x10 6 MS...

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“…Several reports show that cryopreservation reduces the immunomodulatory capacity of MSCs. 18,19 On the other hand, cryopreservation does not alter the surface marker profiles and osteogenic potential of BM-MSCs or compromise the therapeutic effects on cardiac function after direct intramyocardial injection. 20,21 Difference in donors or the cultivation period after cell thawing might affect the characteristics of MSCs.…”

Section: Discussionmentioning

confidence: 99%

Isolation of mesenchymal stromal/stem cells from cryopreserved umbilical cord blood cells

Fujii

Miura

Iwasa

et al. 2017

J Clin Exp Hematopathol

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JC EH lin xp ematopathol Original Article INTRODUCTIONCell therapy using human mesenchymal stromal/stem cells (MSCs) has been extensively explored for the treatment of a variety of diseases based on their multiple biological and therapeutic effects.1 An off-the-shelf allogeneic bone marrow (BM)-derived MSC product is currently available in the clinic for the treatment of the intractable acute graft-versushost disease after hematopoietic stem cell transplantation (HSCT). 2,3 BM is the most commonly used source of MSCs. 4 However, invasive procedures are required to obtain BM cells from donors. Although other sources of MSCs that can be obtained without invasive treatments have been sought, including expulsed placenta and exfoliated teeth, complex procedures with enzymatic digestion are necessary to prepare cells from these tissues. 5,6 The demand for allogeneic MSCs is expected to increase in the future; therefore, appropriate sources of MSCs that can be alternatives to BM need to be explored for the further development of MSCbased therapy.In a previous study, we demonstrated that MSCs can be isolated from freshly donated umbilical cord blood (UCB) units that do not qualify for the Japanese banking system as a hematopoietic stem cell (HSC) source because of their small volume.7 UCB has advantages over other tissues because it can be obtained from donors without invasive procedures, and a simple adhesion method without complex procedures can be used to isolate MSCs. In addition, infrastructure for processing and cryopreserving UCB cells is established in the banking system for HSCT in Japan. More importantly, about 90% of donated UCB units are discarded because they do not meet the requirements for an HSC source in terms of volume and/or cell number. 8 We have further extended our investigation of the availability of such UCB units as a Umbilical cord blood (UCB) has advantages over other tissues because it can be obtained without an invasive procedure and complex processing. We explored the availability of cryopreserved UCB cells as a source of mesenchymal stromal/stem cells (MSCs). MSCs were successfully isolated from six of 30 UCB units (median volume, 34.0 mL; median nucleated cell number, 4.4×10 8 ) that were processed and cryopreserved using CP-1/human serum albumin. This isolation rate was lower than that (57%) from non-cryopreserved UCB cells. The number of nucleated cells before and after hydroxyethyl starch separation, UCB unit volume, and cell viability after thawing did not significantly differ between UCB units from which MSCs were successfully isolated and those from which they were not. When CryoSure-DEX40 was used as a cryoprotectant, MSCs were isolated from two of ten UCB units. Logistic regression analysis demonstrated that the cryopreservation method was not significantly associated with the success of MSC isolation. The isolated MSCs had a similar morphology and surface marker expression profile as bone marrow-derived MSCs and were able to differentiate into osteogenic, adipogenic, and chondro...

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Do Cryopreserved Mesenchymal Stromal Cells Display Impaired Immunomodulatory and Therapeutic Properties?

Cited by 306 publications

References 43 publications

Defining mesenchymal stromal cells responsiveness to IFN^|^gamma; as a surrogate measure of suppressive potency

Defining mesenchymal stromal cells responsiveness to IFN^|^gamma; as a surrogate measure of suppressive potency

Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey

Isolation of mesenchymal stromal/stem cells from cryopreserved umbilical cord blood cells

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