Bone Marrow Stem Cells using in Ukraine
Bone marrow cells reside deep inside bone cavities in
the most protected part of the body and are redundant
throughout the organism. This preferential status reflects
the primary role these cells play in the survival of the
organism. Stem cells from marrow naturally home to,
thrive and proliferate in hypoxic tissue.
(10) In response to
trauma, which creates a hypoxic environment, marrow
cells mobilize into the vasculature from the medullary
space where the cells aggregate themselves into the
recently created hypoxic damaged tissue.
(3-10) Una vez
resident, marrow stem cells are capable of functioning in
the hostile hypoxic environment to orchestrate the tissue
regeneration process. (10)
By capturing all of the nucleated cells through a proper
marrow aspiration, you are maintaining the same relative
proportion of cells that naturally aggregates at the defect
site. The following quote captures the essence of this
insight “These data demonstrate that removing BMSC’s
(bone marrow stem cells) from their normal environment
of complimentary cells reduces their osteoblastic capacity
and that to achieve their maximal di erentiation, BMSC’s
require direct physical contact with accessory cells.”
(2)
Consequently, the potential of marrow-sourced
nucleated cells should be thought of as a group of
di erent cells that is able to:
1) Home to and self organize at the defect site
2) Release the appropriate levels of various growth
factors to influence the function and cytokine production
of resident cells based on the stage of the healing
cascade and
3) Cooperate with and influence resident cells to
accomplish the steps of the healing cascade that
culminates in repair. (1,10, 19-38)
Each nucleated cell type contributes to the process of
tissue repair. (2)
Por ejemplo, granulocytes in the area of
bone regeneration release large amounts of VEFG which
up regulates the production of BMP-2 and BMP-6 by
sub-populations of CD-34 + células. (37,38)
Properly aspirating marrow, and appropriately
administering the cells is significantly enhancing and
exactly mimicking the body’s natural healing process. (10)
This simple explanation is fundamental to the use of
marrow cells in damaged tissue. In the case of bone
grafting, the cells need to be combined with a functional
bone matrix. In the case of osteonecrosis or heart
disease and limb ischemia, the ischemic bone or muscle
serves as the sca old and the cells are directly injected
to the site. (14,16,30) Trauma that does not heal is often
the result of an inadequate number of mobilized marrow
cells at the site of the defect. (11,12)
Autograft exactly mimics and supplements the natural
process in that resident in the harvested bone are the
living cells of the marrow that are cut from one part of the
body and transplanted to another. Autograft is especially
suited for bone repair as the bone from the autograft
serves as an appropriate sca old for the transplanted cells.
In fact, by collagenase digesting human autograft and
counting the cells, Muechler et al demonstrated that
autograft has approximately the number of nucleated
cells per CC and cfu-f as the Marrow CellutionTM needle
aspirate. (29,42) By combining the nucleated cell rich
fraction with a functioning matrix, you create the same
treating composition, (types and ratio of cells) as is
contained in autograft without the morbidity.
By examining all of the cellular components of autograft,
we see that those same cells are contained marrow
aspirate. (29) When we look at the role of those di erent
cells in bone formation, we see that each of the cellular
components of autograft, and thus by extension, marrow,
play a positive role in the micro-environment of bone
formation. Por ejemplo, T-cells and other lymphocytes
improve the mobility and functionality of EPC’s (39, 40) En
addition; some of the most potent stem cells reside in the
deeper granulocytic layer. (28) This is likely because
cycling progenitor cells increase the density of their
nucleus just before going through mitosis. So, capturing
all of the nucleated cells, similar to autograft, is the
optimal strategy.
A review of the literature demonstrates
similar clinical outcomes to autograft when using high
concentrations of nucleated cells from marrow as
measured by cfu-f. Por ejemplo, Hernigou et al in
non-union, Gan et al in multilevel lumbar spine fusion,
Marrow CellutionTM and
A Functional Bone Matrix:
The Power of Synergy Jager et al in orthopedic bone defects, Gangji et al and
Herigou et al in osteonecrosis,Velardi et al for pediatric
skull defects, and Sauerbier et al for sinus lift
augmentation. (13-18,35)
Each cell in a di erent micro-environment can provide a
di erent function; Por ejemplo, granulocytes are
inflammatory in the micro-environment of infection
compared to pro-regeneration in the micro-environment
of building new bone or tissue. (1, 41) Just because a cell
has what could be construed to be a negative impact
such as pro-inflammatory in a di erent
micro-environment( ie granulocytes in an area of
infection), does not mean that cell will have that impact in
another micro-environment such as tissue repair. Recent
insights has focused on the role that marrow stem cells
play in regulating other cells during the immune
reparative processes at the sight of trauma.
(43)
A marrow aspirate that
is e cient at capturing
nucleated cells has the
same number and
types of nucleated
cells as autograft.
Bone marrow cells reside deep inside bone cavities in
the most protected part of the body and are redundant
throughout the organism. This preferential status reflects
the primary role these cells play in the survival of the
organism. Stem cells from marrow naturally home to,
thrive and proliferate in hypoxic tissue. (10) In response to
trauma, which creates a hypoxic environment, marrow
cells mobilize into the vasculature from the medullary
space where the cells aggregate themselves into the
recently created hypoxic damaged tissue. (3-10) Una vez
resident, marrow stem cells are capable of functioning in
the hostile hypoxic environment to orchestrate the tissue
regeneration process. (10)
By capturing all of the nucleated cells through a proper
marrow aspiration, you are maintaining the same relative
proportion of cells that naturally aggregates at the defect
site. The following quote captures the essence of this
insight “These data demonstrate that removing BMSC’s
(bone marrow stem cells) from their normal environment
of complimentary cells reduces their osteoblastic capacity
and that to achieve their maximal di erentiation, BMSC’s
require direct physical contact with accessory cells.” (2)
Consequently, the potential of marrow-sourced
nucleated cells should be thought of as a group of
di erent cells that is able to:
1) Home to and self organize at the defect site
2) Release the appropriate levels of various growth
factors to influence the function and cytokine production
of resident cells based on the stage of the healing
cascade and
3) Cooperate with and influence resident cells to
accomplish the steps of the healing cascade that
culminates in repair. (1,10, 19-38)
Each nucleated cell type contributes to the process of
tissue repair. (2) Por ejemplo, granulocytes in the area of
bone regeneration release large amounts of VEFG which
up regulates the production of BMP-2 and BMP-6 by
sub-populations of CD-34 + células. (37,38)
Properly aspirating marrow, and appropriately
administering the cells is significantly enhancing and
exactly mimicking the body’s natural healing process. (10)
This simple explanation is fundamental to the use of
marrow cells in damaged tissue. In the case of bone
grafting, the cells need to be combined with a functional
bone matrix. In the case of osteonecrosis or heart
disease and limb ischemia, the ischemic bone or muscle
serves as the sca old and the cells are directly injected
to the site. (14,16,30) Trauma that does not heal is often
the result of an inadequate number of mobilized marrow
cells at the site of the defect. (11,12)
Autograft exactly mimics and supplements the natural
process in that resident in the harvested bone are the
living cells of the marrow that are cut from one part of the
body and transplanted to another. Autograft is especially
suited for bone repair as the bone from the autograft
serves as an appropriate sca old for the transplanted cells.
In fact, by collagenase digesting human autograft and
counting the cells, Muechler et al demonstrated that
autograft has approximately the number of nucleated
cells per CC and cfu-f as the Marrow CellutionTM needle
aspirate. (29,42) By combining the nucleated cell rich
fraction with a functioning matrix, you create the same
treating composition, (types and ratio of cells) as is
contained in autograft without the morbidity.
By examining all of the cellular components of autograft,
we see that those same cells are contained marrow
aspirate. (29) When we look at the role of those di erent
cells in bone formation, we see that each of the cellular
components of autograft, and thus by extension, marrow,
play a positive role in the micro-environment of bone
formation. Por ejemplo, T-cells and other lymphocytes
improve the mobility and functionality of EPC’s (39, 40) En
addition; some of the most potent stem cells reside in the
deeper granulocytic layer. (28) This is likely because
cycling progenitor cells increase the density of their
nucleus just before going through mitosis. So, capturing
all of the nucleated cells, similar to autograft, is the
optimal strategy. A review of the literature demonstrates
similar clinical outcomes to autograft when using high
concentrations of nucleated cells from marrow as
measured by cfu-f. Por ejemplo, Hernigou et al in
non-union, Gan et al in multilevel lumbar spine fusion,
Jager et al in orthopedic bone defects, Gangji et al and
Herigou et al in osteonecrosis,Velardi et al for pediatric
skull defects, and Sauerbier et al for sinus lift
augmentation. (13-18,35)
Each cell in a di erent micro-environment can provide a
di erent function; Por ejemplo, granulocytes are
inflammatory in the micro-environment of infection
compared to pro-regeneration in the micro-environment
of building new bone or tissue. (1, 41) Just because a cell
has what could be construed to be a negative impact
such as pro-inflammatory in a di erent
micro-environment( ie granulocytes in an area of
infection), does not mean that cell will have that impact in
another micro-environment such as tissue repair. Recent
insights has focused on the role that marrow stem cells
play in regulating other cells during the immune
reparative processes at the sight of trauma. (43)
Aspirating high quality marrow and
combining it with a functioning matrix
for transplantation into a bone defect is
exactly mimicking and supplementing
the body’s natural response to that
surgical trauma site. Clinical results are
positively correlated to the number of
cfu-f contained in the graft. (15-18,35)
1
Fuentes:
1 Autocrine angiogenic vascular prosthesis with bone marrow transplantation
Noishiki et al Nature Medicine, 2 (1):90-93 (1996)
2 Megakaryocyte-Bone Marrow Stromal Aggregates Demonstrate Increased
Colony Formation and Alkaline Phosphatase Expression in Vitro Dengshun et
al Tissue Engineering; Vol 10 No. 5/6 200424)
3 Adult vasculogenesis occurs through in situ recruitment, proliferación, y
tubulization of circulating bone marrow-derived cells Blood, 1 Febrero 2005, Vol.
105, No. 3, pp. 1068-1077
4 Circulating Bone Marrow-Derived Osteoblast Progenitor Cells Are Recruited to
the Bone Forming Site by the CXCR4/Stromal Cell-Derived Factor –1 Pathway”
Otsuru et al Stem Cells 2008;26 223-234
5 A Systemic Provascular response in Bone Marrow to Musculoskeletal Trauma in
Mice Laing et al Journal of Bone and Joint Surgery – British Volume, Vol 89-B, Issue
1, 116-120
6 Stem Cells and Distraction Osteogenesis: Endothelial Progenitor Cells Home to
the Ischemic Generate in Activation and Consolidation Cetrulo et al Plast Reconstr
Surg. 2005 Sep 15;116(4):1053-64;
7 Expression of Vascular Antigens by bone cells during bone regeneration in a
membranous bone distraction system Lewison et al Histochem Cell Biol 2001 116
381-388
8 “Endochondral ossification in fracture callus during long bone repair: el
localisation of “cavity-lining cells” within the cartilage” Ford et al Journal of
Orthopaedic Research 22 (2004) 368-375.
9 Circulating Mesenchymal Stem Cells In The Fracture Non-Union Patients Chao
Wan et al Journal of Bone and Joint Surgery – British Volume, Vol 88-B, Issue
SUPP_III, 403-404
10 Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured
tissue. Ceradina et al Trends Cardiovasc Med. 2005 Feb;15(2):57-63
11 Dunac A, Frelin C, Popolo-Blondeau M, Chatel M, Mahagne MH, Philip PJ.
Neurological and functional recovery in human stroke are associated with
peripheral blood CD34+ cell mobilization. J Neurol 2007; 254: 327–332.
12 Circulating Endothelial Progenitor Cells, Vascular Function, and Cardiovascular
Risk Jonathan M. Hill, M.R.C.P., Gloria Zalos, R.N., Julian P.J. Halcox, M.R.C.P.,
William H. Schenke, B.A., Myron A. Waclawiw, Doctor., Arshed A. Quyyumi, MARYLAND., y
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13 Percutaneous Autologous Bone-Marrow Grafting for Nonunions, Hernigou, et al
Journal of Bone and Joint Surgery; 87:1430-1437; 2005
14 CLIUCAL STUDY: Treatment of osteonecrosis with autologous bone marrow
grafting Hernigou, et. al.: Clinical Ortho and Related Research; 2002
15 Bone Marrow Concentrate: A Novel Strategy for Bone Defect Treatment M.
Jäger*. Current Stem Cell Research & Therapy, 2009
16 Treatment of osteonecrosis of the femoral head with implantation of autologous
bone marrow cells Gangji, et. al.: Journal of Bone and Joint Surgery; 2004
17 Sinus Augmentation with chair-side processed Mesenchymal Stem Cells,
Sebastian Sauerbier, Rainer Schmelzeisen, Ralf Gutwald, Journal of CranioMaxillofacial Surgery, Supplement, 2008, Vol. 36(S):158
18 Osteogenesis induced by autologous bone marrow cells transplant in the
pediatric skull Velardi et al Pediatric Research. 63(5):497-501, Puede 2008.
19 Zhang, et. al.: “Therapeutic potential of non-adherent BM-derived mesenchymal
stem cells in tissue regeneration” Bone Marrow Transplantation 2009 43 69-81
20 Modder, et. al.; “Skeletal Stem /Osteoprogenitor Cells: Current
concepts,Alternative Hypothesis, and Relationship to the Bone Remodeling
Compartment” : Journal of Cellular Biochemistry 103: 393-400 ; 2008
21 Hematopoietic Stem Cells Regulate Mesenchymal Stromal Cell Induction into
Osteoblasts Thereby Participating in the Formation of the Stem Cell Niche Stem
Cells Younghun Junga Vol. 26 No. 8 Agosto 2008, pp. 2042 –2051
22 Niemeyer et al “Comparison of mesenchymal stem cell from bone marrow and
adipose tissue for bone regeneration in a critical size defect of the sheep tibia and
the influence of platelet rich plasma” Biomaterials 31 2010 3572-3579
23 Tondreau, t. et. al.; Mesenchymal Stem Cells Derived from CD133-Positive Cells in
Mobilized Peripheral Blood and Cord Blood: Proliferación, Oct4 Expression, and Plasticity
24 Células madre ; Vol. 23 No. 8;1105 –1112; Septiembre 2005 Local delivery of GM-PB
Mobilized CD34 + Progenitor Cells Using Biosca old for Modality of Unhealing
Bone Fracture” Mifune et al Stem Cells 2008; 26:1395-1405
25 Therapeutic Potential of Vasculogenesis and Osteogenesis Promoted by
Peripheral Blood CD34-Positive cells for Functional Bone Healing Matsumoto et al
American Journal of Pathology. 2006;169:1440-1457.)
26 Fracture Induced Mobilization and Incorporation of Bone Marrow-Derived
Endothelial Progenitor Cells for Bone Healing” Matsumotot et al J Cell Physiol.
2008 Apr;215(1):234-42.
27 Amanda C. LaRue et al Hematopoietic origins of fibroblasts: I. In vivo studies of
fibroblasts associated with solid tumors Experimental Hematology 34 (2006)
208–218
28 Isolation of Bone Marrow Derived Stem Cells Using Density Gradient
Separación. Juopperi et al Experimental Hematology , 2007 Volumen 35 , Issue 2 ,
Pages 335 – 341
29 Comparison of bone marrow aspiration and bone core biopsy as methods for
Harvest and Assay of Human Connective Tissue Progenitors Rozic et al Cleveland
Clinic NIH grant RO1 AR049686
30 “Therapeutic Angiogenesis for Patients with Limb Ischemia by Autlogous
Transplantation of Bone Marrow Cells: A Pilot Study and Randomized Controlled
Study”, Yuyama, et al, The Lancet; 360:427-435; 2002
31 Midterm clinical result of tissue-engineered vascular autografts seeded with
autologous bone marrow cells; Toshiharu et al. J Thorac Cardiovasc Surg
2005;129:1330-1338
32 Shinji Yasuhara et al E cacy of Bone Marrow Mononuclear Cells to Promote
Bone Regeneration Compared With Isolated CD34+ Cells From the Same Volume
of Aspirate Artificial Organs 34(7):594–599, Wiley Periodicals, Cª.
33 Bogt, et. al.; Comparison of Di erent Adult Stem Cell Types for Treatment of
MyocardialIschemia: Circulation; 118: 121-129; 2008Hermann et al
34 Concentration of bone marrow total nucleated cells by a point-of-care device
provides a high yield and preserves their functional activity. Cell Transplantation
(2008) Volumen: 16, Issue: 10, Pages: 1059-1069
35 Gan et al The clinical use of enriched bone marrow stem cells combined with
porous beta-tricalcium phosphate in posterior spinal fusion Biomaterials 29 (2008)
3973–3982
36 Boukhechba Fate of Bone Marrow Stromal Cells in a Syngenic Model of Bone
Formation Tissue Engineering Volume: 17 Issue 17-18: Agosto 25, 2011
37 Platelets and Granulocytes, in Particular the Neutrophils, Form Important
Compartments for Circulating Vascular Endothelial Growth Factor Kusumanto, et
al. ANGIOGENESIS 6(4):283-287 2004
38 Bouletreau et al Hypoxia and VEGF Up-Regulate BMP-2 mRNA and Protein
Expression in Microvascular Endothelial Cells: Implications for Fracture Healing
Plastic & Reconstructive Surgery: Junio 2002 – Volumen 109 – Issue 7 – pp
2384-2397 38)
39 Identification of a Novel Role of T Cells in Postnatal Vasculogenesis:
Charaterization of Endothelial Progenitor Cell Colonies” Hur et al Circulation 2007
116; 1671-1682
40 “CD+8 Lymphocytes Regulate the Arteriogentic Response to Ischemia by
Infiltrating the Site of Collateral Vessel Development and Recruiting CD4+
Mononuclear Cells Through the Expression of Interleukin 16” Stabile et al
Circulation 2006;113; 118-124
41 Tissue Augmentation by White Blood Cell-Containing Platelet-Rich Plasma
Kawazoe et alCell Transplantation, Vol. 21, pp. 601–607, 2012
42 Annual Orthopedic Update 2016, Allegheny Health Network; ”Marrow
CellutionTM Bone Marrow Aspiration System and Related Concentrations of Stem
and Progenitor Cells”. Lecture- Machael A Scarpone MD, Daniel Kuebler
43 Bone-Derived Stem Cells Repair the Heart After Myocardial Infarction Through
Transdi erentiation and Paracrine Signaling Mechanisms Duran et al, Integrative
Physiology Circulation Research.2013; 113: 539-552
B
