Macrophage heterogeneity in the single-cell era: facts and artifacts

2.

Grabert

K

,

Sehgal

A

,

Irvine

KM

, et al.

A transgenic line that reports CSF1R protein expression provides a definitive marker for the mouse mononuclear phagocyte system

.

J Immunol

.

2020

;

205

(

11

):

3154

-

3166

.

3.

Summers

KM

,

Bush

SJ

,

Hume

DA

.

Network analysis of transcriptomic diversity amongst resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

.

PLoS Biol

.

2020

;

18

(

10

):

e3000859

.

4.

Mass

E

,

Nimmerjahn

F

,

Kierdorf

K

,

Schlitzer

A

.

Tissue-specific macrophages: how they develop and choreograph tissue biology

.

Nat Rev Immunol

.

2023

:

1

-

17

.

5.

Hume

DA

.

Differentiation and heterogeneity in the mononuclear phagocyte system

.

Mucosal Immunol

.

2008

;

1

(

6

):

432

-

441

.

6.

Hume

DA

,

Irvine

KM

,

Pridans

C

.

The mononuclear phagocyte system: the relationship between monocytes and macrophages

.

Trends Immunol

.

2019

;

40

(

2

):

98

-

112

.

7.

Sehgal

A

,

Carter-Cusack

D

,

Keshvari

S

, et al.

Fate-mapping studies in inbred mice: a model for understanding macrophage development and homeostasis?

.

Eur J Immunol

.

2023

;

53

(

8

):

e2250312

.

8.

Ng

LG

,

Liu

Z

,

Kwok

I

,

Ginhoux

F

.

Origin and heterogeneity of tissue myeloid cells: a focus on GMP-derived monocytes and neutrophils

.

Annu Rev Immunol

.

2023

;

41

:

375

-

404

.

9.

Guilliams

M

,

Thierry

GR

,

Bonnardel

J

,

Bajenoff

M

.

Establishment and maintenance of the macrophage niche

.

Immunity

.

2020

;

52

(

3

):

434

-

451

.

10.

Ginhoux

F

,

Yalin

A

,

Dutertre

CA

,

Amit

I

.

Single-cell immunology: past, present, and future

.

Immunity

.

2022

;

55

(

3

):

393

-

404

.

11.

Sanin

DE

,

Ge

Y

,

Marinkovic

E

, et al.

A common framework of monocyte-derived macrophage activation

.

Sci Immunol

.

2022

;

7

(

70

):

eabl7482

.

12.

Dick

SA

,

Wong

A

,

Hamidzada

H

, et al.

Three tissue resident macrophage subsets coexist across organs with conserved origins and life cycles

.

Sci Immunol

.

2022

;

7

(

67

):

eabf7777

.

13.

Bassler

K

,

Schulte-Schrepping

J

,

Warnat-Herresthal

S

,

Aschenbrenner

AC

,

Schultze

JL

.

The myeloid cell compartment-cell by cell

.

Annu Rev Immunol

.

2019

;

37

:

269

-

293

.

14.

Keshvari

S

,

Caruso

M

,

Teakle

N

, et al.

CSF1R-dependent macrophages control postnatal somatic growth and organ maturation

.

PLoS Genet

.

2021

;

17

(

6

):

e1009605

.

15.

Rojo

R

,

Raper

A

,

Ozdemir

DD

, et al.

Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations

.

Nat Commun

.

2019

;

10

(

1

):

3215

.

16.

Haimon

Z

,

Volaski

A

,

Orthgiess

J

, et al.

Re-evaluating microglia expression profiles using RiboTag and cell isolation strategies

.

Nat Immunol

.

2018

;

19

(

6

):

636

-

644

.

17.

Millard

SM

,

Heng

O

,

Opperman

KS

, et al.

Fragmentation of tissue-resident macrophages during isolation confounds analysis of single-cell preparations from mouse hematopoietic tissues

.

Cell Rep

.

2021

;

37

(

8

):

110058

.

18.

Mondor

I

,

Baratin

M

,

Lagueyrie

M

, et al.

Lymphatic endothelial cells are essential components of the subcapsular sinus macrophage niche

.

Immunity

.

2019

;

50

(

6

):

1453

-

1466.e4

.

19.

Batoon

L

,

Millard

SM

,

Wullschleger

ME

, et al.

CD169(+) macrophages are critical for osteoblast maintenance and promote intramembranous and endochondral ossification during bone repair

.

Biomaterials

.

2019

;

196

:

51

-

66

.

20.

Kaur

S

,

Raggatt

LJ

,

Batoon

L

,

Hume

DA

,

Levesque

JP

,

Pettit

AR

.

Role of bone marrow macrophages in controlling homeostasis and repair in bone and bone marrow niches

.

Semin Cell Dev Biol

.

2017

;

61

:

12

-

21

.

21.

Tabula Muris Consortium

.

Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris

.

Nature

.

2018

;

562

(

7727

):

367

-

372

.

22.

Han

X

,

Wang

R

,

Zhou

Y

, et al.

Mapping the mouse cell atlas by Microwell-seq

.

Cell

.

2018

;

172

(

5

):

1091

-

1107.e1017

.

23.

Han

X

,

Zhou

Z

,

Fei

L

, et al.

Construction of a human cell landscape at single-cell level

.

Nature

.

2020

;

581

(

7808

):

303

-

309

.

24.

Gray

EE

,

Friend

S

,

Suzuki

K

,

Phan

TG

,

Cyster

JG

.

Subcapsular sinus macrophage fragmentation and CD169+ bleb acquisition by closely associated IL-17-committed innate-like lymphocytes

.

PLoS One

.

2012

;

7

(

6

):

e38258

.

25.

Baccin

C

,

Al-Sabah

J

,

Velten

L

, et al.

Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization

.

Nat Cell Biol

.

2020

;

22

(

1

):

38

-

48

.

26.

Li

W

,

Wang

Y

,

Zhao

H

, et al.

Identification and transcriptome analysis of erythroblastic island macrophages

.

Blood

.

2019

;

134

(

5

):

480

-

491

.

27.

Romano

L

,

Seu

KG

,

Papoin

J

, et al.

Erythroblastic islands foster granulopoiesis in parallel to terminal erythropoiesis

.

Blood

.

2022

;

140

(

14

):

1621

-

1634

.

28.

Tay

J

,

Bisht

K

,

McGirr

C

, et al.

Imaging flow cytometry reveals that granulocyte colony-stimulating factor treatment causes loss of erythroblastic islands in the mouse bone marrow

.

Exp Hematol

.

2020

;

82

:

33

-

42

.

29.

Popescu

DM

,

Botting

RA

,

Stephenson

E

, et al.

Decoding human fetal liver haematopoiesis

.

Nature

.

2019

;

574

(

7778

):

365

-

371

.

30.

Pinho

S

,

Wei

Q

,

Maryanovich

M

, et al.

VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells

.

Nat Cell Biol

.

2022

;

24

(

3

):

290

-

298

.

31.

Pinho

S

,

Marchand

T

,

Yang

E

,

Wei

Q

,

Nerlov

C

,

Frenette

PS

.

Lineage-biased hematopoietic stem cells are regulated by distinct niches

.

Dev Cell

.

2018

;

44

(

5

):

634

-

641.e4

.

32.

Tikhonova

AN

,

Dolgalev

I

,

Hu

H

, et al.

The bone marrow microenvironment at single-cell resolution

.

Nature

.

2019

;

569

(

7755

):

222

-

228

.

33.

Nestorowa

S

,

Hamey

FK

,

Pijuan Sala

B

, et al.

A single-cell resolution map of mouse hematopoietic stem and progenitor cell differentiation

.

Blood

.

2016

;

128

(

8

):

e20

-

31

.

34.

Hernandez-Malmierca

P

,

Vonficht

D

,

Schnell

A

, et al.

Antigen presentation safeguards the integrity of the hematopoietic stem cell pool

.

Cell Stem Cell

.

2022

;

29

(

5

):

760

-

775.e10

.

35.

Lynch

RW

,

Hawley

CA

,

Pellicoro

A

,

Bain

CC

,

Iredale

JP

,

Jenkins

SJ

.

An efficient method to isolate Kupffer cells eliminating endothelial cell contamination and selective bias

.

J Leukoc Biol

.

2018

;

104

(

3

):

579

-

586

.

36.

Bleriot

C

,

Barreby

E

,

Dunsmore

G

, et al.

A subset of Kupffer cells regulates metabolism through the expression of CD36

.

Immunity

.

2021

;

54

(

9

):

2101

-

2116.e6

.

37.

De Simone

G

,

Andreata

F

,

Bleriot

C

, et al.

Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming

.

Immunity

.

2021

;

54

(

9

):

2089

-

2100.e8

.

38.

Liang

Y

,

Kaneko

K

,

Xin

B

, et al.

Temporal analyses of postnatal liver development and maturation by single-cell transcriptomics

.

Dev Cell

.

2022

;

57

(

3

):

398

-

414.e5

.

39.

Hume

DA

,

Offermanns

S

,

Bonnavion

R

.

Contamination of isolated mouse Kupffer cells with liver sinusoidal endothelial cells

.

Immunity

.

2022

;

55

(

7

):

1139

-

1140

.

40.

Iannacone

M

,

Bleriot

C

,

Andreata

F

, et al.

Response to contamination of isolated mouse Kupffer cells with liver sinusoidal endothelial cells

.

Immunity

.

2022

;

55

(

7

):

1141

-

1142

.

41.

Guilliams

M

,

Bonnardel

J

,

Haest

B

, et al.

Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches

.

Cell

.

2022

;

185

(

2

):

379

-

396.e38

.

42.

Bonnardel

J

,

T'Jonck

W

,

Gaublomme

D

, et al.

Stellate cells, hepatocytes, and endothelial cells imprint the Kupffer cell identity on monocytes colonizing the liver macrophage niche

.

Immunity

.

2019

;

51

(

4

):

638

-

654.e9

.

43.

Sakai

M

,

Troutman

TD

,

Seidman

JS

, et al.

Liver-derived signals sequentially reprogram myeloid enhancers to initiate and maintain Kupffer cell identity

.

Immunity

.

2019

;

51

(

4

):

655

-

670.e8

.

44.

Terkelsen

MK

,

Bendixen

SM

,

Hansen

D

, et al.

Transcriptional dynamics of hepatic sinusoid-associated cells after liver injury

.

Hepatology

.

2020

;

72

(

6

):

2119

-

2133

.

45.

Kolodziejczyk

AA

,

Federici

S

,

Zmora

N

, et al.

Acute liver failure is regulated by MYC- and microbiome-dependent programs

.

Nat Med

.

2020

;

26

(

12

):

1899

-

1911

.

46.

Zhou

Y

,

Adewale

F

,

Kim

S

, et al.

Five-in-one: simultaneous isolation of multiple major liver cell types from livers of normal and NASH mice

.

J Cell Mol Med

.

2021

;

25

(

20

):

9878

-

9883

.

47.

Zong

C

,

Meng

Y

,

Ye

F

, et al.

AIF1(+) CSF1R(+) MSCs, induced by TNF-alpha, act to generate an inflammatory microenvironment and promote hepatocarcinogenesis

.

Hepatology

.

2023

;

78

(

2

):

434

-

451

.

48.

Kumar

V

,

Donthireddy

L

,

Marvel

D

, et al.

Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors

.

Cancer Cell

.

2017

;

32

(

5

):

654

-

668.e5

.

49.

Tang

PC

,

Chung

JY

,

Liao

J

, et al.

Single-cell RNA sequencing uncovers a neuron-like macrophage subset associated with cancer pain

.

Sci Adv

.

2022

;

8

(

40

):

eabn5535

.

50.

Bain

CC

,

MacDonald

AS

.

The impact of the lung environment on macrophage development, activation and function: diversity in the face of adversity

.

Mucosal Immunol

.

2022

;

15

(

2

):

223

-

234

.

51.

Aegerter

H

,

Lambrecht

BN

,

Jakubzick

CV

.

Biology of lung macrophages in health and disease

.

Immunity

.

2022

;

55

(

9

):

1564

-

1580

.

52.

Tan

SY

,

Krasnow

MA

.

Developmental origin of lung macrophage diversity

.

Development

.

2016

;

143

(

8

):

1318

-

1327

.

53.

Irvine

KM

,

Caruso

M

,

Cestari

MF

, et al.

Analysis of the impact of CSF-1 administration in adult rats using a novel Csf1r-mApple reporter gene

.

J Leukoc Biol

.

2020

;

107

(

2

):

221

-

235

.

54.

Sikkema

L

,

Ramirez-Suastegui

C

,

Strobl

DC

, et al.

An integrated cell atlas of the lung in health and disease

.

Nat Med

.

2023

;

29

(

6

):

1563

-

1577

.

55.

Hume

PS

,

Gibbings

SL

,

Jakubzick

CV

, et al.

Localization of macrophages in the human lung via design-based stereology

.

Am J Respir Crit Care Med

.

2020

;

201

(

10

):

1209

-

1217

.

56.

Baillie

JK

,

Arner

E

,

Daub

C

, et al.

Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease

.

PLoS Genet

.

2017

;

13

(

3

):

e1006641

.

57.

Chakarov

S

,

Lim

HY

,

Tan

L

, et al.

Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches

.

Science

.

2019

;

363

(

6432

):

eaau0964

.

58.

Schyns

J

,

Bai

Q

,

Ruscitti

C

, et al.

Non-classical tissue monocytes and two functionally distinct populations of interstitial macrophages populate the mouse lung

.

Nat Commun

.

2019

;

10

(

1

):

3964

.

59.

Leach

SM

,

Gibbings

SL

,

Tewari

AD

, et al.

Human and mouse transcriptome profiling identifies cross-species homology in pulmonary and lymph node mononuclear phagocytes

.

Cell Rep

.

2020

;

33

(

5

):

108337

.

60.

Vanneste

D

,

Bai

Q

,

Hasan

S

, et al.

MafB-restricted local monocyte proliferation precedes lung interstitial macrophage differentiation

.

Nat Immunol

.

2023

;

24

(

5

):

827

-

840

.

61.

Ural

BB

,

Yeung

ST

,

Damani-Yokota

P

, et al.

Identification of a nerve-associated, lung-resident interstitial macrophage subset with distinct localization and immunoregulatory properties

.

Sci Immunol

.

2020

;

5

(

45

):

eaax8756

.

62.

Fantom Consortium

.

A promoter-level mammalian expression atlas

.

Nature

.

2014

;

507

(

7493

):

462

-

470

.

63.

Cheung

MD

,

Erman

EN

,

Moore

KH

, et al.

Resident macrophage subpopulations occupy distinct microenvironments in the kidney

.

JCI Insight

.

2022

;

7

(

20

):

e161078

.

64.

Sarkar

A

,

Stephens

M

.

Separating measurement and expression models clarifies confusion in single-cell RNA sequencing analysis

.

Nat Genet

.

2021

;

53

(

6

):

770

-

777

.

65.

Abadie

K

,

Pease

NA

,

Wither

MJ

,

Kueh

HY

.

Order by chance: origins and benefits of stochasticity in immune cell fate control

.

Curr Opin Syst Biol

.

2019

;

18

:

95

-

103

.

66.

Hume

DA

.

Probability in transcriptional regulation and its implications for leukocyte differentiation and inducible gene expression

.

Blood

.

2000

;

96

(

7

):

2323

-

2328

.

67.

Raj

A

,

van Oudenaarden

A

.

Nature, nurture, or chance: stochastic gene expression and its consequences

.

Cell

.

2008

;

135

(

2

):

216

-

226

.

68.

Helft

J

,

Bottcher

J

,

Chakravarty

P

, et al.

GM-CSF mouse bone marrow cultures comprise a heterogeneous population of CD11c(+)MHCII(+) macrophages and dendritic cells

.

Immunity

.

2015

;

42

(

6

):

1197

-

1211

.

69.

Shalek

AK

,

Satija

R

,

Adiconis

X

, et al.

Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells

.

Nature

.

2013

;

498

(

7453

):

236

-

240

.

70.

Shalek

AK

,

Satija

R

,

Shuga

J

, et al.

Single-cell RNA-seq reveals dynamic paracrine control of cellular variation

.

Nature

.

2014

;

510

(

7505

):

363

-

369

.

71.

Ravasi

T

,

Wells

C

,

Forest

A

, et al.

Generation of diversity in the innate immune system: macrophage heterogeneity arises from gene-autonomous transcriptional probability of individual inducible genes

.

J Immunol

.

2002

;

168

(

1

):

44

-

50

.

72.

Ding

J

,

Sharon

N

,

Bar-Joseph

Z

.

Temporal modelling using single-cell transcriptomics

.

Nat Rev Genet

.

2022

;

23

(

6

):

355

-

368

.

73.

Jenkins

SJ

,

Allen

JE

.

The expanding world of tissue-resident macrophages

.

Eur J Immunol

.

2021

;

51

(

8

):

1882

-

1896

.

74.

Ke

M

,

Elshenawy

B

,

Sheldon

H

,

Arora

A

,

Buffa

FM

.

Single cell RNA-sequencing: a powerful yet still challenging technology to study cellular heterogeneity

.

Bioessays

.

2022

;

44

(

11

):

e2200084

.

75.

Grabski

IN

,

Street

K

,

Irizarry

RA

.

Significance analysis for clustering with single-cell RNA-sequencing data

.

Nat Methods

.

2023

;

20

(

8

):

1196

-

1202

.

76.

Xi

NM

,

Li

JJ

.

Benchmarking computational doublet-detection methods for single-cell RNA sequencing data

.

Cell Syst

.

2021

;

12

(

2

):

176

-

194.e6

.

77.

Freeman

TC

,

Horsewell

S

,

Patir

A

, et al.

Graphia: a platform for the graph-based visualisation and analysis of high dimensional data

.

PLoS Comput Biol

.

2022

;

18

(

7

):

e1010310

.

78.

Reshef

YA

,

Rumker

L

,

Kang

JB

, et al.

Co-varying neighborhood analysis identifies cell populations associated with phenotypes of interest from single-cell transcriptomics

.

Nat Biotechnol

.

2022

;

40

(

3

):

355

-

363

.

79.

Van Hove

H

,

Martens

L

,

Scheyltjens

I

, et al.

A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment

.

Nat Neurosci

.

2019

;

22

(

6

):

1021

-

1035

.

80.

Wu

YE

,

Pan

L

,

Zuo

Y

,

Li

X

,

Hong

W

.

Detecting activated cell populations using single-cell RNA-seq

.

Neuron

.

2017

;

96

(

2

):

313

-

329.e6

.

81.

Koenitzer

JR

,

Wu

H

,

Atkinson

JJ

,

Brody

SL

,

Humphreys

BD

.

Single-nucleus RNA-sequencing profiling of mouse lung. Reduced dissociation bias and improved rare cell-type detection compared with single-cell RNA sequencing

.

Am J Respir Cell Mol Biol

.

2020

;

63

(

6

):

739

-

747

.

82.

Stewart

TA

,

Hughes

K

,

Hume

DA

,

Davis

FM

.

Developmental stage-specific distribution of macrophages in mouse mammary gland

.

Front Cell Dev Biol

.

2019

;

7

:

250

.

83.

Sehgal

A

,

Donaldson

DS

,

Pridans

C

,

Sauter

KA

,

Hume

DA

,

Mabbott

NA

.

The role of CSF1R-dependent macrophages in control of the intestinal stem-cell niche

.

Nat Commun

.

2018

;

9

(

1

):

1272

.